FLUOROGENIC AMINO ACIDS

Abstract

Provided herein are compounds (i.e., fluorogenic amino acids (FgAAs), e.g., compounds of Formulae (I), (II), (III), and (IV)) that can be used in fluorescent labeling of biomolecules (e.g., proteins) and/or cells. Also described herein are methods of labeling and detecting biomolecules and/or cells by incorporating the FgAA compounds described herein into the biomolecules and/or cells (e.g., by enzymatic incorporation). Also provided herein are biomolecules, cells, compositions, and kits comprising the FgAA compounds described herein.

Claims

1. A compound of Formula (I): ##STR00216## or a salt, tautomer, or isotopically labeled derivative thereof, wherein: ═Y.sup.A is ═N.sup.+(R.sup.N1).sub.2, ═NR.sup.N1, ═O.sup.+R.sup.O1, ═O, or ═S.sup.+R.sup.S1, or ═S; Ring A is an optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl ring comprising at least one double bond in conjugation with ═Y.sup.A and the group: ##STR00217## Ring B is optionally substituted aryl or optionally substituted heteroaryl ring; Y.sup.B is —N(R.sup.N1).sub.2, —OR.sup.O1, or —SR.sup.S1; L.sup.1 is a bond, optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted carbocyclylene, optionally substituted arylene, optionally substituted heterocyclylene optionally substituted heteroarylene, optionally substituted acylene, or a combination thereof; R.sup.1 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, an oxygen protecting group, an amino acid, or a polypeptide; each instance of R.sup.2 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, a nitrogen protecting group, an amino acid, or a polypeptide; or two R.sup.2 bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; each instance of R.sup.N1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group; or two R.sup.N1 bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; each instance of R.sup.O1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or an oxygen protecting group; and each instance of R.sup.S1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a sulfur protecting group.

2. The compound of the preceding claim, wherein Ring A is a 6-membered optionally substituted carbocyclic or 6-membered optionally substituted heterocyclic ring.

3. The compound of any one of the preceding claims, wherein the compound is of the formula: ##STR00218## or a salt, tautomer, or isotopically labeled derivative thereof, wherein: each of X.sup.1, X.sup.2, X.sup.3, and X.sup.4 are independently N or CR.sup.4; each instance of R.sup.4 is independently hydrogen, halogen, —CN, —NO.sub.2, —N.sub.3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, sulfate, sulfonate, —N(R.sup.N).sub.2, —OR.sup.O, or —SR.sup.S; each instance of R.sup.N is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group; or two R.sup.N bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; each instance of R.sup.O is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or an oxygen protecting group; and each instance of R.sup.S is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a sulfur protecting group.

4. The compound of any one of the preceding claims, wherein X.sup.1 is CR.sup.4.

5. The compound of any one of the preceding claims, wherein X.sup.2 is CR.sup.4.

6. The compound of any one of the preceding claims, wherein X.sup.3 is CR.sup.4.

7. The compound of any one of the preceding claims, wherein X.sup.4 is CR.sup.4.

8. The compound of any one of the preceding claims, wherein Ring A is an optionally substituted C.sub.6 carbocyclic ring.

9. The compound of any one of the preceding claims, wherein Ring A is an optionally substituted cyclohexadienyl ring.

10. The compound of any one of the preceding claims, wherein Ring A is of the formula: ##STR00219## wherein: each instance of R.sup.4 is independently hydrogen, halogen, —CN, —NO.sub.2, —N.sub.3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, sulfate, sulfonate, —N(R.sup.N).sub.2, —OR.sup.O, or —SR.sup.S; each instance of R.sup.N is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group; or two R.sup.N bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; each instance of R.sup.O is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or an oxygen protecting group; each instance of R.sup.S is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a sulfur protecting group; and m is 0, 1, 2, 3, or 4.

11. The compound of any one of the preceding claims, wherein Ring B is optionally substituted aryl.

12. The compound of any one of the preceding claims, wherein Ring B is optionally substituted phenyl.

13. The compound of any one of the preceding claims, wherein Ring B is of the formula: ##STR00220## wherein: each instance of R.sup.4 is independently hydrogen, halogen, —CN, —NO.sub.2, —N.sub.3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, sulfate, sulfonate, —N(R.sup.N).sub.2, —OR.sup.O, or —SR.sup.S; each instance of R.sup.N is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group; or two R.sup.N bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; each instance of R.sup.O is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or an oxygen protecting group; each instance of R.sup.S is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a sulfur protecting group; and m is 0, 1, 2, 3, or 4.

14. The compound of any one of the preceding claims, wherein the compound is of the formula: ##STR00221## or a salt, tautomer, or isotopically labeled derivative thereof.

15. The compound of any one of the preceding claims, wherein ═Y.sup.A is ═N.sup.+(R.sup.N1).sub.2.

16. The compound of any one of the preceding claims, wherein ═Y.sup.A is ═O.

17. The compound of any one of the preceding claims, wherein Y.sup.B is —N(R.sup.N1).sub.2.

18. The compound of any one of the preceding claims, wherein Y.sup.B is —OR.sup.O1.

19. The compound of any one of the preceding claims, wherein the compound is of one of the following formulae: ##STR00222## or a salt, tautomer, or isotopically labeled derivative thereof.

20. The compound of any one of the preceding claims, wherein L.sup.1 is optionally substituted alkylene.

21. The compound of any one of the preceding claims, wherein L.sup.1 is optionally substituted C.sub.1-6 alkylene.

22. The compound of any one of the preceding claims, wherein L.sup.1 is unsubstituted C.sub.1-6 alkylene.

23. The compound of any one of the preceding claims, wherein L.sup.1 is of the formula: ##STR00223##

24. The compound of any one of the preceding claims, wherein L.sup.1 is of the formula: ##STR00224##

25. The compound of any one of the preceding claims, wherein L.sup.1 is of the formula: ##STR00225##

26. The compound of any one of the preceding claims, wherein L.sup.1 is of the formula: ##STR00226##

27. The compound of any one of the preceding claims, wherein the compound is of one of the following formulae: ##STR00227## or a salt, tautomer, or isotopically labeled derivative thereof, wherein: n is an integer from 1-6, inclusive.

28. The compound of any one of the preceding claims, wherein the compound is of one of the following formulae: ##STR00228## or a salt, tautomer, or isotopically labeled derivative thereof, wherein: n is an integer from 1-6, inclusive.

29. The compound of any one of the preceding claims, wherein the compound is of the following formula: ##STR00229## or a salt, tautomer, or isotopically labeled derivative thereof, wherein: n is an integer from 1-6, inclusive.

30. The compound of claim 1, wherein the compound is of one of the following formulae: ##STR00230## or a salt, tautomer, or isotopically labeled derivative thereof, wherein p is 0, 1, 2, 3, 4, 5, or 6.

31. The compound of claim 1, wherein the compound is of the following formula: ##STR00231## or a salt, tautomer, or isotopically labeled derivative thereof; wherein s is 0, 1, 2, 3, 4, 5, or 6; and p is 0, 1, 2, 3, 4, 5, or 6.

32. The compound of claim 1, wherein the compound is of the following formula: ##STR00232## or a salt, tautomer, or isotopically labeled derivative thereof; wherein s is 0, 1, 2, 3, 4, 5, or 6.

33. The compound of claim 1, wherein the compound is of the following formula: ##STR00233## or a salt, tautomer, or isotopically labeled derivative thereof; wherein s is 0, 1, 2, 3, 4, 5, or 6; and p is 0, 1, 2, 3, 4, 5, or 6.

34. The compound of claim 1, wherein the compound is of the following formula: ##STR00234## or a salt, tautomer, or isotopically labeled derivative thereof; wherein s is 0, 1, 2, 3, 4, 5, or 6; and p is 0, 1, 2, 3, 4, 5, or 6.

35. The compound of claim 1, wherein the compound is of the following formula: ##STR00235## or a salt, tautomer, or isotopically labeled derivative thereof; wherein s is 0, 1, 2, 3, 4, 5, or 6; and p is 0, 1, 2, 3, 4, 5, or 6.

36. The compound of any one of the preceding claims, wherein each instance of m is 0.

37. The compound of any one of the preceding claims, wherein at least one instance of R.sup.N1 is optionally substituted alkyl.

38. The compound of any one of the preceding claims, wherein at least one instance of R.sup.N1 is optionally substituted C.sub.1-6 alkyl.

39. The compound of any one of the preceding claims, wherein at least one instance of R.sup.N1 is unsubstituted C.sub.1-6 alkyl.

40. The compound of any one of the preceding claims, wherein at least one instance of R.sup.N1 is methyl.

41. The compound of any one of the preceding claims, wherein each instance of R.sup.N1 is methyl.

42. The compound of any one of the preceding claims, wherein at least one instance of R.sup.O1 is hydrogen.

43. The compound of any one of the preceding claims, wherein the compound is of one of the following formulae: ##STR00236## or a salt, tautomer, or isotopically labeled derivative thereof, wherein: n is an integer from 1-6, inclusive.

44. The compound of any one of the preceding claims, wherein the compound is of one of the following formulae: ##STR00237## or a salt, tautomer, or isotopically labeled derivative thereof, wherein: n is an integer from 1-6, inclusive.

45. The compound of any one of the preceding claims, wherein the compound is of the following formula: ##STR00238## or a salt, tautomer, or isotopically labeled derivative thereof, wherein:

46. The compound of any one of the preceding claims, wherein n is 1, 2, or 3.

47. The compound of any one of the preceding claims, wherein the compound is of one of the following formulae: ##STR00239## or a salt, tautomer, or isotopically labeled derivative thereof.

48. The compound of any one of the preceding claims, wherein the compound is of one of the following formulae: ##STR00240## or a salt, tautomer, or isotopically labeled derivative thereof.

49. The compound of any one of the preceding claims, wherein the compound is of the formula: ##STR00241## or a salt, tautomer, or isotopically labeled derivative thereof.

50. The compound of any one of the preceding claims, wherein R.sup.1 is hydrogen.

51. The compound of any one of the preceding claims, wherein at least one instance of R.sup.2 is hydrogen.

52. The compound of any one of the preceding claims, wherein each instance of R.sup.2 is hydrogen.

53. The compound of claim 1, wherein the compound is selected from the group consisting of: ##STR00242## ##STR00243## and salts, tautomers, or isotopically labeled derivatives thereof.

54. A compound of Formula (II): ##STR00244## or a salt, tautomer, or isotopically labeled derivative thereof, wherein: Ring D is optionally substituted aryl or optionally substituted heteroaryl; R.sup.3 is hydrogen, ═NR.sup.NX, —N—R.sup.NX, ═S, —S.sup.−, ═O, —O.sup.−, ═C(R.sup.C).sub.2, halogen, —CN, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or optionally substituted acyl; custom-character is a single or double bond, provided that when is a single bond, R.sup.3 is ═NR.sup.NX ═S, ═O or ═C(R.sup.C).sub.2, and provided that when is a double bond, R.sup.3 is not ═NR.sup.NX, ═S, ═O or ═C(R.sup.C).sub.2; Ring C is an optionally substituted heterocyclic or heteroaryl ring comprising at least one N, S, or O atom; wherein the heterocyclic or heteroaryl ring is in conjugation with the group: ##STR00245## Ring C is an optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl ring substituted with custom-character Y.sup.C and comprising at least one double bond in conjugation with Y.sup.C and the group: ##STR00246## Y.sup.C is —N(R.sup.N1).sub.2, ═N.sup.+(R.sup.N1).sub.2, ═NR.sup.N1.sub.2—OR.sup.O1, ═O.sup.+R.sup.O1, ═O, —SR.sup.S1, ═S.sup.+R.sup.S1, or ═S; Y is a bond, —O—, —NR.sup.N2—, or —S—; L.sup.2 is a bond, optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted carbocyclylene, optionally substituted arylene, optionally substituted heterocyclylene, optionally substituted heteroarylene, optionally substituted acylene, or a combination thereof; R.sup.1 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, an oxygen protecting group, an amino acid, or a polypeptide; each instance of R.sup.2 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, a nitrogen protecting group, an amino acid, or a polypeptide; or two R.sup.2 bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; each instance of R.sup.N1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group; or two R.sup.N1 bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; R.sup.N2 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group; R.sup.NX is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group; each instance of R.sup.O1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or an oxygen protecting group; each instance of R.sup.S1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a sulfur protecting group; and each instance of R.sup.C is independently hydrogen, halogen, —CN, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or optionally substituted acyl; optionally wherein two R.sup.C on the same carbon atom are joined together with the intervening atoms to form optionally substituted carbocyclyl or optionally substituted heterocyclyl.

55. The compound of any one of the preceding claims, wherein Ring C is a 6-membered optionally substituted carbocyclic or 6-membered optionally substituted heterocyclic ring substituted with custom-character Y.sup.C.

56. The compound of any one of the preceding claims, wherein the compound is of one of the following formula: ##STR00247## or a salt, tautomer, or isotopically labeled derivative thereof, wherein: each of X.sup.1, X.sup.2, X.sup.3, and X.sup.4 are independently N or CR.sup.4; each instance of R.sup.4 is independently hydrogen, halogen, —CN, —NO.sub.2, —N.sub.3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, sulfate, sulfonate, —N(R.sup.N).sub.2, —OR.sup.O, or —SR.sup.S; each instance of R.sup.N is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group; or two R.sup.N bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; each instance of R.sup.O is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or an oxygen protecting group; and each instance of R.sup.S is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a sulfur protecting group.

57. The compound of any one of the preceding claims, wherein the compound is of the formula: ##STR00248## or a salt, tautomer, or isotopically labeled derivative thereof, wherein: each instance of R.sup.4 is independently hydrogen, halogen, —CN, —NO.sub.2, —N.sub.3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, sulfate, sulfonate, —N(R.sup.N).sub.2, —OR.sup.O, or —SR.sup.S; each instance of R.sup.N is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group; or two R.sup.N bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; each instance of R.sup.O is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or an oxygen protecting group; each instance of R.sup.S is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a sulfur protecting group; and m is 0, 1, 2, 3, or 4.

58. The compound of any one of the preceding claims, wherein the compound is of the formula: ##STR00249## or a salt, tautomer, or isotopically labeled derivative thereof.

59. The compound of any one of the preceding claims, wherein X.sup.1 is CR.sup.4.

60. The compound of any one of the preceding claims, wherein X.sup.2 is CR.sup.4.

61. The compound of any one of the preceding claims, wherein X.sup.3 is CR.sup.4.

62. The compound of any one of the preceding claims, wherein X.sup.4 is CR.sup.4.

63. The compound of any one of the preceding claims, wherein Ring C is an optionally C.sub.6 carbocyclic ring.

64. The compound of any one of the preceding claims, wherein Ring C is an optionally substituted cyclohexadienyl ring.

65. The compound of any one of the preceding claims, wherein Ring C is of the formula: ##STR00250## wherein: each instance of R.sup.4 is independently hydrogen, halogen, —CN, —NO.sub.2, —N.sub.3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, sulfate, sulfonate, —N(R.sup.N).sub.2, —OR.sup.O, or —SR.sup.S; each instance of R.sup.N is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group; or two R.sup.N bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; each instance of R.sup.O is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or an oxygen protecting group; each instance of R.sup.S is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a sulfur protecting group; and m is 0, 1, 2, 3, or 4.

66. The compound of any one of the preceding claims, wherein the compound is of the formula: ##STR00251## or a salt, tautomer, or isotopically labeled derivative thereof.

67. The compound of any one of the preceding claims, wherein ═Y.sup.C is ═N.sup.+(R.sup.N1).sub.2.

68. The compound of any one of the preceding claims, wherein the compound is of the formula: ##STR00252## or a salt, tautomer, or isotopically labeled derivative thereof.

69. The compound of any one of the preceding claims, wherein the compound is of the formula: ##STR00253## or a salt, tautomer, or isotopically labeled derivative thereof.

70. The compound of any one of the preceding claims, wherein the compound is of the formula: ##STR00254## or a salt, tautomer, or isotopically labeled derivative thereof, wherein n is an integer from 1-6, inclusive.

71. The compound of any one of the preceding claims, wherein the compound is of the following formula: ##STR00255## or a salt, tautomer, or isotopically labeled derivative thereof.

72. The compound of any one of the preceding claims, wherein the compound is of the formula: ##STR00256## or a salt, tautomer, or isotopically labeled derivative thereof, wherein p is 0, 1, 2, 3, 4, 5, or 6.

73. The compound of any one of the preceding claims, wherein at least one instance of R.sup.N1 is hydrogen.

74. The compound of any one of the preceding claims, wherein each instance of R.sup.N1 is hydrogen.

75. The compound of any one of the preceding claims, wherein the compound is of the formula: ##STR00257## or a salt, tautomer, or isotopically labeled derivative thereof.

76. The compound of any one of the preceding claims, wherein the compound is of the formula: ##STR00258## or a salt, tautomer, or isotopically labeled derivative thereof.

77. The compound of any one of the preceding claims, wherein Ring C is an optionally substituted heterocyclic ring.

78. The compound of any one of the preceding claims, wherein Ring C is an optionally substituted 5-membered heterocyclic ring.

79. The compound of any one of the preceding claims, wherein Ring C is of the formula: ##STR00259## wherein each of G.sup.1, G.sup.2, G.sup.3, and G.sup.4 is independently selected from the group consisting of O, S, and NR.sup.N3; and each instance of R.sup.N3 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group.

80. The compound of any one of the preceding claims, wherein the compound is of the formula: ##STR00260## or a salt, tautomer, or isotopically labeled derivative thereof.

81. The compound of any one of the preceding claims, wherein Ring D is optionally substituted aryl.

82. The compound of any one of the preceding claims, wherein Ring D is optionally substituted phenyl.

83. The compound of any one of the preceding claims, wherein Ring D is of the formula: ##STR00261## wherein: each instance of R.sup.4 is independently hydrogen, halogen, —CN, —NO.sub.2, —N.sub.3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, sulfate, sulfonate, —N(R.sup.N).sub.2, —OR.sup.O, or —SR.sup.S; each instance of R.sup.N is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group; or two R.sup.N bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; each instance of R.sup.O is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or an oxygen protecting group; each instance of R.sup.S is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a sulfur protecting group; and m is 0, 1, 2, 3, or 4.

84. The compound of any one of the preceding claims, wherein the compound is of the formula: ##STR00262## or a salt, tautomer, or isotopically labeled derivative thereof.

85. The compound of any one of the preceding claims, wherein the compound is of the formula: ##STR00263## or a salt, tautomer, or isotopically labeled derivative thereof.

86. The compound of any one of the preceding claims, wherein G.sup.1 is S.

87. The compound of any one of the preceding claims, wherein G.sup.2 is NR.sup.N3.

88. The compound of any one of the preceding claims, wherein G.sup.3 is S.

89. The compound of any one of the preceding claims, wherein G.sup.4 is O.

90. The compound of any one of the preceding claims, wherein the compound is of the formula: ##STR00264## or a salt, tautomer, or isotopically labeled derivative thereof.

91. The compound of any one of the preceding claims, wherein Y is —NR.sup.N2—.

92. The compound of any one of the preceding claims, wherein the compound is of the formula: ##STR00265## or a salt, tautomer, or isotopically labeled derivative thereof.

93. The compound of any one of the preceding claims, wherein L.sup.2 is optionally substituted alkylene.

94. The compound of any one of the preceding claims, wherein L.sup.2 is optionally substituted C.sub.1-6 alkylene.

95. The compound of any one of the preceding claims, wherein L.sup.2 is unsubstituted C.sub.1-6 alkylene.

96. The compound of any one of the preceding claims, wherein the compound is of the formula: ##STR00266## or a salt, tautomer, or isotopically labeled derivative thereof, wherein n is an integer from 1-6, inclusive.

97. The compound of any one of the preceding claims, wherein each instance of m is 0.

98. The compound of any one of the preceding claims, wherein each instance of R.sup.4 is hydrogen.

99. The compound of any one of the preceding claims, wherein R.sup.N2 is hydrogen.

100. The compound of any one of the preceding claims, wherein each instance of R.sup.N3 is hydrogen.

101. The compound of any one of the preceding claims, wherein the compound is of the formula: ##STR00267## or a salt, tautomer, or isotopically labeled derivative thereof.

102. The compound of any one of the preceding claims, wherein n is 1, 2, or 3.

103. The compound of any one of the preceding claims, wherein the compound is of the formula: ##STR00268## or a salt, tautomer, or isotopically labeled derivative thereof.

104. The compound of any one of the preceding claims, wherein R.sup.1 is hydrogen.

105. The compound of any one of the preceding claims, wherein at least one instance of R.sup.2 is hydrogen.

106. The compound of any one of the preceding claims, wherein each instance of R.sup.2 is hydrogen.

107. The compound of any one of the preceding claims, wherein custom-character is a single bond; and R.sup.3 is ═O.

108. The compound of any one of the preceding claims, wherein custom-character a double bond.

109. The compound of any one of the preceding claims, wherein custom-character is a double bond; and R.sup.3 is hydrogen.

110. The compound of any one of the preceding claims, wherein the compound is selected from the group consisting of: ##STR00269## ##STR00270## and salts, tautomers, and isotopically labeled derivatives thereof.

111. A compound of Formula (III): ##STR00271## and salts, tautomers, and isotopically labeled derivatives thereof, wherein: R.sup.3 is ═NR.sup.NX, ═S, ═O, or ═C(R.sup.C).sub.2; —Y.sup.C is —N(R.sup.N1).sub.2, —OR.sup.O1, or —SR.sup.S1; L.sup.2 is a bond, optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted carbocyclylene, optionally substituted arylene, optionally substituted heterocyclylene, optionally substituted heteroarylene, optionally substituted acylene, or a combination thereof; R.sup.1 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, an oxygen protecting group, an amino acid, or a polypeptide; each instance of R.sup.2 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, a nitrogen protecting group, an amino acid, or a polypeptide; or two R.sup.2 bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; each instance of R.sup.N1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group; or two R.sup.N1 bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; R.sup.N2 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group; R.sup.NX is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group; each instance of R.sup.O1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or an oxygen protecting group; each instance of R.sup.S1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a sulfur protecting group; each instance of R.sup.C is independently hydrogen, halogen, —CN, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or optionally substituted acyl, optionally wherein two R.sup.C on the same carbon atom are joined together with the intervening atoms to form optionally substituted carbocyclyl or optionally substituted heterocyclyl; each instance of R.sup.4 is independently hydrogen, halogen, —CN, —NO.sub.2, —N.sub.3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl optionally substituted sulfonyl, optionally substituted sulfinyl, sulfate, sulfonate, —N(R.sup.N).sub.2, —OR.sup.O, or —SR.sup.S; each instance of R.sup.N is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group; or two R.sup.N bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; each instance of R.sup.O is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or an oxygen protecting group; each instance of R.sup.S is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a sulfur protecting group; and m is 0, 1, 2, 3, or 4.

112. The compound of any one of the preceding claims, wherein compound is of one of the following formulae: ##STR00272## or a salt, tautomer, or isotopically labeled derivative thereof.

113. A compound of Formula (IV): ##STR00273## or a salt, tautomer, or isotopically labeled derivative thereof, wherein: Ring C is an optionally substituted aryl ring, or optionally substituted heteroaryl ring comprising at least one N, S, or O atom; wherein Ring C is substituted with —Y.sup.C; Y.sup.C is —N(R.sup.N1).sub.2, —OR.sup.O1, —SR.sup.S1, each of G.sup.1, G.sup.3, and G.sup.4 is independently selected from the group consisting of O, S, and NR.sup.N3; G.sup.2 is N; R.sup.3 is hydrogen, halogen, —CN, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or optionally substituted acyl; L.sup.2 is a bond, optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted carbocyclylene, optionally substituted arylene, optionally substituted heterocyclylene, optionally substituted heteroarylene, optionally substituted acylene, or a combination thereof; R.sup.1 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, an oxygen protecting group, an amino acid, or a polypeptide; each instance of R.sup.2 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, a nitrogen protecting group, an amino acid, or a polypeptide; or two R.sup.2 bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; each instance of R.sup.N1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group; or two R.sup.N1 bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; each instance of R.sup.O1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or an oxygen protecting group; each instance of R.sup.S1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a sulfur protecting group; each instance of R.sup.N3 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group.

114. The compound of any one of the preceding claims, wherein the compound is of the formula: ##STR00274## or a salt, tautomer, or isotopically derivative thereof, wherein: each instance of R.sup.4 is independently hydrogen, halogen, —CN, —NO.sub.2, —N.sub.3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl optionally substituted sulfonyl, optionally substituted sulfinyl, sulfate, sulfonate, —N(R.sup.N).sub.2, —OR.sup.O, or —SR.sup.S; each instance of R.sup.N is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group; or two R.sup.N bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; each instance of R.sup.O is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or an oxygen protecting group; each instance of R.sup.S is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a sulfur protecting group; and m is 0, 1, 2, 3, or 4.

115. The compound of any one of the preceding claims, wherein the compound is one of the following formulae: ##STR00275## or a salt, tautomer, or isotopically derivative thereof.

116. The compound of any one of the preceding claims, wherein the compound is a D-amino acid.

117. The compound of any one of the preceding claims, wherein the compound is an L-amino acid.

118. A composition comprising a compound of any one of the preceding claims; and a solvent or excipient.

119. A biomolecule comprising a compound of any one of the preceding claims, or a salt or a tautomer thereof, wherein the compound is covalently attached to to the biomolecule.

120. The biomolecule of any one of the preceding claims, wherein the biomolecule is a protein, polypeptide, glycan, peptidoglycan, antibody, or nucleic acid.

121. The biomolecule of any one of the preceding claims, wherein the biomolecule is a protein.

122. The biomolecule of any one of the preceding claims, wherein the biomolecule is peptidoglycan.

123. A cell comprising a compound of any one of the preceding claims, or a salt, tautomer, or isotopically labeled derivative thereof.

124. The cell of any one of the preceding claims, wherein the cell is a mammalian cell.

125. The cell of any one of the preceding claims, wherein the cell is a bacterial cell.

126. A method of labeling a biomolecule, the method comprising exposing the biomolecule and/or cell to a compound of any one of the preceding claims, or a salt, tautomer, or isotopically labeled derivative thereof.

127. The method of any one of the preceding claims, wherein the compound is covalently incorporated into the biomolecule.

128. The method of any one of the preceding claims, wherein the compound is incorporated into biomolecule via enzymatic incorporation.

129. The method of any one of the preceding claims, where the compound is incorporated into the biomolecule through transpeptidation.

130. The method of any one of the preceding claims, wherein the compound is incorporated into a protein, polypeptide, or peptidoglycan via transpeptidation.

131. The method of any one of the preceding claims, wherein the compound is incorporated into peptidoglycan.

132. The method of any one of the preceding claims, where the compound is incorporated into the biomolecule and/or cell through D,D-transpeptidation or L,D-transpeptidation.

133. A method of labeling a cell, the method comprising exposing the cell to a compound of any one of the preceding claims, or a salt, tautomer, or isotopically labeled derivative thereof.

134. The method of any one of the preceding claims, wherein the compound is covalently incorporated into the cell.

135. The method of any one of the preceding claims, wherein the compound is incorporated into the cell via enzymatic incorporation.

136. The method of any one of the preceding claims, where the compound is incorporated into the cell through transpeptidation.

137. The method of any one of the preceding claims, wherein the compound is incorporated into a protein, polypeptide, or peptidoglycan via transpeptidation.

138. The method of any one of the preceding claims, wherein the compound is incorporated into peptidoglycan.

139. The method of any one of the preceding claims, where the compound is incorporated into the biomolecule and/or cell through D,D-transpeptidation or L,D-transpeptidation.

140. A method of detecting a biomolecule and/or cell comprising: (a) labeling the biomolecule or cell according to a method of any one of the preceding claims; and (b) measuring the fluorescence of the biomolecule and/or cell.

141. The method of any one of the preceding claims, wherein the biomolecule is a protein, polypeptide, or peptidoglycan

142. A method of detecting a labeled biomolecule or cell of any one of the preceding claims, the method comprising measuring or observing the fluorescence of the biomolecule or cell.

143. The method of any one of the preceding claims, wherein the biomolecule is a protein.

144. The method of any one of the preceding claims, wherein the biomolecule is peptidoglycan.

145. The method of any one of the preceding claims, wherein the cell is mammalian cell.

146. The method of any one of the preceding claims, wherein the cell is a bacterial cell.

147. A kit comprising a compound of any one of the preceding claims, or a salt, tautomer, or isotopically labeled derivative thereof, or a composition thereof; and one or more chemical reagents or enzymes.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0090] The accompanying drawings, which constitute a part of this specification, illustrate several embodiments of the invention and together with the description, serve to explain the principles of the invention.

[0091] FIG. 1. Enhanced green fluorescent protein (EGFP) requires maturation and in some instances is approximately 100× larger than some of the fluorogenic amino acid (FgAA) compounds provided herein.

[0092] FIG. 2. FgAA compounds described herein can be similar in size to many non-standard amino acids (nsAAs) that can be encoded into proteins in live cells, e.g., BpA. Fold “turn-on” values for exemplary FgAAs are shown.

[0093] FIGS. 3A-3C. Design of exemplary FgAAs (FIG. 3A). As shown, the exemplary compounds “turn on” in glycerol (FIG. 3B) or when incorporated to bacterial cell walls (FIG. 3C).

[0094] FIG. 4. Generic structures representing certain embodiments of FgAAs provided herein.

[0095] FIG. 5. Generic structures representing certain embodiments of FgAAs provided herein.

[0096] FIGS. 6A-6D. Excitation and absorbance data for exemplary FgAAs (Molecules a-e). Relative fluorescent units (RFU) is normalized using ‘RFU glycerol’ for each molecule independently.

[0097] FIG. 7. Normalized absorbance spectra for and structures of Molecules a and b. ** Molecule b likely has an absorbance maximum beyond the detection limit of the instrument

[0098] FIG. 8. Absorbance spectra for and structures of Molecules c and d.

[0099] FIG. 9. Normalized absorbance spectra for and structures of Molecules c and d.

[0100] FIG. 10. Summary of fluorescence fold increase data. Fold increase in fluorescence was calculated by dividing relative fluorescence units (RFU) in glycerol (95% final) by RFU in Phosphate Buffered Saline (PBS) at the same concentrations of dye. Averages of 4 independent measurements were shown. * Indicates the average RFU value in PBS was negative after subtracting the blank. Therefore the value of 1 was assumed for RFU in PBS.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0101] Provided herein are compounds (i.e., fluorogenic amino acids (FgAAs), e.g., compounds of Formulae (I), (II), (III), and (IV)) that can be used in fluorescent labeling of biomolecules and/or cells. Also described herein are methods of labeling and/or detecting biomolecules and/or cells by incorporating the FgAA compounds described herein into the biomolecules and/or cells (e.g., by enzymatic incorporation). Also provided herein are biomolecules, cells, compositions, and kits comprising the FgAA compounds described herein.

[0102] Small, rapidly-maturing FgAA labeling reagents provided herein address many of the challenges associated with current labeling technologies. A critical problem with current technologies is the high background signal originating from unbound probes. In contrast, the FgAAs provided herein activate, or “turn on,” upon incorporation into biomolecules or macromolecules, thereby minimizing or eliminating background noise. The FgAAs have an emission intensity that is sensitive to the ability of the environment the fluorophore is in to restrict bond rotation (“spatial hindrance”). In certain embodiments, the FgAAs provided herein allow for the detection/monitoring biomolecules and cells in real time and with minimal perturbation.

Fluorogenic Amino Acids

[0103] Provided herein are compounds of Formula (I):

##STR00009##

and salts, tautomers, and isotopically labeled derivatives thereof, wherein: [0104] ═Y.sup.A is ═N.sup.+(R.sup.N1).sub.2, ═NR.sup.N1, ═O.sup.+R.sup.O1, ═O, or ═S.sup.+R.sup.S1, or ═S; [0105] Ring A is an optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl ring comprising at least one double bond in conjugation with ═Y.sup.A and the group:

##STR00010## [0106] Ring B is optionally substituted aryl or optionally substituted heteroaryl ring; [0107] Y.sup.B is —N(R.sup.N1).sub.2, —OR.sup.O1, or —SR.sup.S1; [0108] L.sup.1 is a bond, optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkynylene, optionally substituted carbocyclylene, optionally substituted arylene, optionally substituted heterocyclylene optionally substituted heteroarylene, optionally substituted acylene, or a combination thereof; [0109] R.sup.1 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, an oxygen protecting group, an amino acid, or a polypeptide; [0110] each instance of R.sup.2 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, a nitrogen protecting group, an amino acid, or a polypeptide; or two R.sup.2 bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; [0111] each instance of R.sup.N1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group; or two R.sup.N1 bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; [0112] each instance of R.sup.O1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or an oxygen protecting group; and [0113] each instance of R.sup.S1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a sulfur protecting group.

[0114] In certain embodiments, the compound of Formula (I) is of one of the following formulae:

##STR00011##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0115] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00012##

or a salt, tautomer, or isotopically labeled derivative thereof, wherein: [0116] each of X.sup.1, X.sup.2, X.sup.3, and X.sup.4 are independently N or CR.sup.4; [0117] each instance of R.sup.4 is independently hydrogen, halogen, —CN, —NO.sub.2, —N.sub.3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, sulfate, sulfonate, —N(R.sup.N).sub.2, —OR.sup.O, or —SR.sup.S; [0118] each instance of R.sup.N is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group; or two R.sup.N bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; [0119] each instance of R.sup.O is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or an oxygen protecting group; and [0120] each instance of R.sup.S is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a sulfur protecting group.

[0121] In certain embodiments, the compound of Formula (I) is of one of the following formulae:

##STR00013##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0122] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00014##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0123] In certain embodiments, the compound of Formula (I) is of one of the following formulae:

##STR00015##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0124] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00016##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0125] In certain embodiments, the compound of Formula (I) is of one of the following formulae:

##STR00017##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0126] In certain embodiments, the compound of Formula (I) is of one of the following formulae:

##STR00018##

or a salt, tautomer, or isotopically labeled derivative thereof, wherein: [0127] n is an integer from 1-6, inclusive.

[0128] In certain embodiments, the compound of Formula (I) is of one of the following formulae:

##STR00019##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0129] In certain embodiments, the compound of Formula (I) is of one of the following formulae:

##STR00020##

or a salt, tautomer, or isotopically labeled derivative thereof, wherein: [0130] n is an integer from 1-6, inclusive.

[0131] In certain embodiments, the compound of Formula (I) is of one of the following formulae:

##STR00021##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0132] In certain embodiments, the compound of Formula (I) is of one of the following formulae:

##STR00022##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0133] As described herein, the compounds may be in the form of their tautomers, for example, as shown below:

##STR00023##

[0134] In certain embodiments, the compound of Formula (I) is of one of the following formulae:

##STR00024##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0135] In certain embodiments, the compound of Formula (I) is of one of the following formulae:

##STR00025##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0136] As described herein, the compounds may be in the form of their tautomers, for example, as shown below:

##STR00026##

[0137] In certain embodiments, the compound of Formula (I) is of one of the following formulae:

##STR00027##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0138] As described herein, the compounds may be in the form of their tautomers, for example, as shown below:

##STR00028##

[0139] In certain embodiments, the compound of Formula (I) is of one of the following formulae:

##STR00029##

or a salt, tautomer, or isotopically labeled derivative thereof, wherein: [0140] n is an integer from 1-6, inclusive.

[0141] In certain embodiments, the compound of Formula (I) is of one of the following formulae:

##STR00030##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0142] In certain embodiments, the compound of Formula (I) is of one of the following formulae:

##STR00031##

or a salt, tautomer, or isotopically labeled derivative thereof, wherein: [0143] n is an integer from 1-6, inclusive.

[0144] In certain embodiments, the compound of Formula (I) is of one of the following formulae:

##STR00032##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0145] In certain embodiments, the compound of Formula (I) is of one of the following formulae:

##STR00033##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0146] In certain embodiments, the compound of Formula (I) is of one of the following formulae:

##STR00034##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0147] In certain embodiments, the compound of Formula (I) is of one of the following formulae:

##STR00035##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0148] In certain embodiments, the compound of Formula (I) is of one of the following formulae:

##STR00036##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0149] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00037##

or a salt, tautomer, or isotopically labeled derivative thereof, wherein: [0150] n is an integer from 1-6, inclusive.

[0151] In certain embodiments, the compound of Formula (I) is of one of the following formulae:

##STR00038##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0152] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00039##

or a salt, tautomer, or isotopically labeled derivative thereof, wherein: [0153] n is an integer from 1-6, inclusive.

[0154] In certain embodiments, the compound of Formula (I) is of one of the following formulae:

##STR00040##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0155] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00041##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0156] In certain embodiments, the compound of Formula (I) is of one of the following formulae:

##STR00042##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0157] In certain embodiments, the compound of Formula (I) is of one of the following formulae:

##STR00043##

or a salt, tautomer, or isotopically labeled derivative thereof, wherein p is 0, 1, 2, 3, 4, 5, or 6.

[0158] In certain embodiments, the compound of Formula (I) is of the following formula:

##STR00044##

or a salt, tautomer, or isotopically labeled derivative thereof; wherein s is 0, 1, 2, 3, 4, 5, or 6.

[0159] In certain embodiments, the compound of Formula (I) is of one of the following formulae:

##STR00045##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0160] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00046##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0161] In certain embodiments, the compound of Formula (I) is of one of the following formulae:

##STR00047##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0162] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00048##

or a salt, tautomer, or isotopically labeled derivative thereof; wherein s is 0, 1, 2, 3, 4, 5, or 6.

[0163] In certain embodiments, the compound of Formula (I) is of one of the following formulae:

##STR00049##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0164] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00050##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0165] In certain embodiments, the compound of Formula (I) is of one of the following formulae:

##STR00051##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0166] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00052##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0167] In certain embodiments, the compound of Formula (I) is of one of the following formulae:

##STR00053##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0168] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00054##

or a salt, tautomer, or isotopically labeled derivative thereof; wherein s is 0, 1, 2, 3, 4, 5, or 6;
and p is 0, 1, 2, 3, 4, 5, or 6.

[0169] In certain embodiments, the compound of Formula (I) is of one of the following formulae:

##STR00055##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0170] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00056##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0171] In certain embodiments, the compound of Formula (I) is of one of the following formulae:

##STR00057##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0172] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00058##

or a salt, tautomer, or isotopically labeled derivative thereof; wherein s is 0, 1, 2, 3, 4, 5, or 6; and p is 0, 1, 2, 3, 4, 5, or 6.

[0173] In certain embodiments, the compound of Formula (I) is of one of the following formulae:

##STR00059##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0174] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00060##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0175] In certain embodiments, the compound of Formula (I) is of one of the following formulae:

##STR00061##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0176] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00062##

or a salt, tautomer, or isotopically labeled derivative thereof; wherein s is 0, 1, 2, 3, 4, 5, or 6; and p is 0, 1, 2, 3, 4, 5, or 6.

[0177] In certain embodiments, the compound of Formula (I) is of one of the following formulae:

##STR00063##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0178] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00064##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0179] In certain embodiments, the compound of Formula (I) is of one of the following formulae:

##STR00065##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0180] Also provided herein are compounds of Formula (II):

##STR00066##

and salts, tautomers, and isotopically labeled derivatives thereof, wherein: [0181] Ring D is optionally substituted aryl or optionally substituted heteroaryl; [0182] R.sup.3 is hydrogen, ═NR.sup.NX, —N—R.sup.NX, ═S, —S—, ═O, —O—, ═C(R.sup.C).sub.2, halogen, —CN, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or optionally substituted acyl; [0183] custom-character is a single or double bond, provided that when is a single bond, R.sup.3 is ═O or ═C(R.sup.C).sub.2, and provided that when is a double bond, R.sup.3 is not ═NR.sup.NX, ═S, ═O or ═C(R.sup.C).sub.2; [0184] Ring C is an optionally substituted heterocyclic or heteroaryl ring comprising at least one N, S, or O atom; wherein the heterocyclic or heteroaryl ring is in conjugation with the group:

##STR00067##

or [0185] Ring C is an optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl ring substituted with custom-character Y.sup.C and comprising at least one double bond in conjugation with Y.sup.C and the group:

##STR00068## [0186] custom-character Y.sup.C is —N(R.sup.N1).sub.2, ═N.sup.+(R.sup.N1).sub.2, ═NR.sup.N1.sub.2—OR.sup.O1, ═O.sup.+R.sup.O1, ═O, —SR.sup.S1, ═S.sup.+R.sup.S1, or ═S; [0187] Y is a bond, —O—, —NR.sup.N2—, or —S—; [0188] L.sup.2 is a bond, optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted carbocyclylene, optionally substituted arylene, optionally substituted heterocyclylene, optionally substituted heteroarylene, optionally substituted acylene, or a combination thereof; [0189] R.sup.1 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, an oxygen protecting group, an amino acid, or a polypeptide; [0190] each instance of R.sup.2 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, a nitrogen protecting group, an amino acid, or a polypeptide; or two R.sup.2 bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; [0191] each instance of R.sup.N1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group; or two R.sup.N1 bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; [0192] R.sup.N2 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group; [0193] R.sup.NX is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group; [0194] each instance of R.sup.O1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or an oxygen protecting group; [0195] each instance of R.sup.S1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a sulfur protecting group; [0196] each instance of R.sup.C is independently hydrogen, halogen, —CN, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or optionally substituted acyl, optionally wherein two R.sup.C on the same carbon atom are joined together with the intervening atoms to form optionally substituted carbocyclyl or optionally substituted heterocyclyl.

[0197] In certain embodiments, the compound of Formula (II) is of one of the following formulae:

##STR00069##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0198] In certain embodiments, the compound of Formula (II) is of the formula:

##STR00070##

or a salt, tautomer, or isotopically labeled derivative thereof, wherein: [0199] each of X.sup.1, X.sup.2, X.sup.3, and X.sup.4 are independently N or CR.sup.4; [0200] each instance of R.sup.4 is independently hydrogen, halogen, —CN, —NO.sub.2, —N.sub.3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, sulfate, sulfonate, —N(R.sup.N).sub.2, —OR.sup.O, or —SR.sup.S; [0201] each instance of R.sup.N is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group; or two R.sup.N bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; [0202] each instance of R.sup.O is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or an oxygen protecting group; and [0203] each instance of R.sup.S is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a sulfur protecting group.

[0204] In certain embodiments, the compound of Formula (II) is of one of the following formulae:

##STR00071##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0205] In certain embodiments, the compound of Formula (II) is of the formula:

##STR00072##

or a salt, tautomer, or isotopically labeled derivative thereof, wherein: [0206] each instance of R.sup.4 is independently hydrogen, halogen, —CN, —NO.sub.2, —N.sub.3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl optionally substituted sulfonyl, optionally substituted sulfinyl, sulfate, sulfonate, —N(R.sup.N).sub.2, —OR.sup.O, or —SR.sup.S; [0207] each instance of R.sup.N is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group; or two R.sup.N bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; [0208] each instance of R.sup.O is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or an oxygen protecting group; [0209] each instance of R.sup.S is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a sulfur protecting group; and [0210] m is 0, 1, 2, 3, or 4.

[0211] In certain embodiments, the compound of Formula (II) is of one of the following formulae:

##STR00073##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0212] In certain embodiments, the compound of Formula (II) is of the formula:

##STR00074##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0213] In certain embodiments, the compound of Formula (II) is of one of the following formulae:

##STR00075##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0214] In certain embodiments, the compound of Formula (II) is of the formula:

##STR00076##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0215] In certain embodiments, the compound of Formula (II) is of one of the following formulae:

##STR00077##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0216] In certain embodiments, the compound of Formula (II) is of the formula:

##STR00078##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0217] In certain embodiments, the compound of Formula (II) is of one of the following formulae:

##STR00079##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0218] In certain embodiments, the compound of Formula (II) is of one of the following formulae:

##STR00080##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0219] In certain embodiments, the compound of Formula (II) is of one of the following formulae:

##STR00081##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0220] In certain embodiments, the compound of Formula (II) is of one of the following formulae:

##STR00082##

or a salt, tautomer, or isotopically labeled derivative thereof, [0221] wherein n is an integer from 1-6, inclusive.

[0222] In certain embodiments, the compound of Formula (II) is of one of the following formulae:

##STR00083##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0223] In certain embodiments, the compound of Formula (II) is of one of the following formulae:

##STR00084##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0224] In certain embodiments, the compound of Formula (II) is of one of the following formulae:

or a salt, tautomer, or isotopically labeled derivative thereof.

##STR00085##

[0225] In certain embodiments, the compound of Formula (II) is of one of the following formulae:

##STR00086##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0226] As described herein, the compounds may be in the form of their tautomers, for example, as shown below:

##STR00087##

[0227] In certain embodiments, the compound of Formula (II) is of one of the following formulae:

##STR00088##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0228] In certain embodiments, the compound of Formula (II) is of the formula:

##STR00089##

or a salt, tautomer, or isotopically labeled derivative thereof, [0229] wherein each of G.sup.1, G.sup.2, G.sup.3, and G.sup.4 is independently selected from the group consisting of O, S, and NR.sup.N3; and [0230] each instance of R.sup.N3 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group.

[0231] In certain embodiments, the compound of Formula (II) is of one of the following formulae:

##STR00090##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0232] In certain embodiments, the compound of Formula (II) is of the formula:

##STR00091##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0233] In certain embodiments, the compound of Formula (II) is of one of the following formulae:

##STR00092##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0234] In certain embodiments, the compound of Formula (II) is of the formula:

##STR00093##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0235] In certain embodiments, the compound of Formula (II) is of one of the following formulae:

##STR00094##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0236] In certain embodiments, the compound of Formula (II) is of the formula:

##STR00095##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0237] In certain embodiments, the compound of Formula (II) is of one of the following formulae:

##STR00096##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0238] In certain embodiments, the compound of Formula (II) is of the formula:

##STR00097##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0239] In certain embodiments, the compound of Formula (II) is of one of the following formulae:

##STR00098##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0240] In certain embodiments, the compound of Formula (II) is of the formula:

##STR00099##

or a salt, tautomer, or isotopically labeled derivative thereof, [0241] wherein n is an integer from 1-6, inclusive.

[0242] In certain embodiments, the compound of Formula (II) is of one of the following formulae:

##STR00100##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0243] In certain embodiments, the compound of Formula (II) is of the formula:

##STR00101##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0244] In certain embodiments, the compound of Formula (II) is of one of the following formulae:

##STR00102##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0245] In certain embodiments, the compound of Formula (II) is of the formula:

##STR00103##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0246] In certain embodiments, the compound of Formula (II) is of one of the following formulae:

##STR00104##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0247] In certain embodiments, the compound of Formula (II) is selected from the group consisting of:

##STR00105##

and salts, tautomers, and isotopically labeled derivatives thereof.

[0248] In certain embodiments, the compound of Formula (II) is selected from the group consisting of:

##STR00106## ##STR00107##

and salts, tautomers, and isotopically labeled derivatives thereof.

[0249] As described herein, the compounds may be in the form of their tautomers, for example, as shown below:

##STR00108##

[0250] In certain embodiments, the compound of Formula (II) is of the following formula:

##STR00109##

or a salt, tautomer, or isotopically labeled derivative thereof, wherein p is 0, 1, 2, 3, 4, 5, or 6.

[0251] In certain embodiments, the compound of Formula (II) is of one of the following formulae:

##STR00110##

or a salt, tautomer, or isotopically labeled derivative thereof, wherein p is 0, 1, 2, 3, 4, 5, or 6.

[0252] In certain embodiments, the compound of Formula (II) is of one of the following formulae:

##STR00111##

or a salt, tautomer, or isotopically labeled derivative thereof, wherein p is 0, 1, 2, 3, 4, 5, or 6.

[0253] Provided herein are compounds of Formula (III):

##STR00112##

and salts, tautomers, and isotopically labeled derivatives thereof, wherein: [0254] R.sup.3 is ═NR.sup.NX, ═S, ═O, or ═C(R.sup.C).sub.2; [0255] —Y.sup.C is —N(R.sup.N1).sub.2, —OR.sup.O1, or —SR.sup.S1; [0256] L.sup.2 is a bond, optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted carbocyclylene, optionally substituted arylene, optionally substituted heterocyclylene, optionally substituted heteroarylene, optionally substituted acylene, or a combination thereof; [0257] R.sup.1 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, an oxygen protecting group, an amino acid, or a polypeptide; [0258] each instance of R.sup.2 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, a nitrogen protecting group, an amino acid, or a polypeptide; or two R.sup.2 bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; [0259] R.sup.N1 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group; or two R.sup.N1 bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; [0260] R.sup.N2 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group; [0261] R.sup.NX is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group; [0262] each instance of R.sup.O1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or an oxygen protecting group; [0263] each instance of R.sup.S1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a sulfur protecting group; [0264] each instance of R.sup.C is independently hydrogen, halogen, —CN, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or optionally substituted acyl, optionally wherein two R.sup.C on the same carbon atom are joined together with the intervening atoms to form optionally substituted carbocyclyl or optionally substituted heterocyclyl; [0265] each instance of R.sup.4 is independently hydrogen, halogen, —CN, —NO.sub.2, —N.sub.3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl optionally substituted sulfonyl, optionally substituted sulfinyl, sulfate, sulfonate, —N(R.sup.N).sub.2, —OR.sup.O, or —SR.sup.S; [0266] each instance of R.sup.N is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group; or two R.sup.N bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; [0267] each instance of R.sup.O is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or an oxygen protecting group; [0268] each instance of R.sup.S is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a sulfur protecting group; and [0269] m is 0, 1, 2, 3, or 4.

[0270] In certain embodiments, the compound of Formula (III) is of the following formula:

##STR00113##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0271] In certain embodiments, the compound of Formula (III) is of one of the following formulae:

##STR00114##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0272] In certain embodiments, the compound of Formula (III) is one of the following:

or a salt, tautomer, or isotopically labeled derivative thereof.

##STR00115##

[0273] In certain embodiments, the compound of Formula (III) is of one of the following formulae:

##STR00116##

or a salt, tautomer, or isotopically labeled derivative thereof.

[0274] Also provided herein are compounds of Formula (IV):

##STR00117##

and salts, tautomers, and isotopically labeled derivatives thereof, wherein: [0275] Ring C is an optionally substituted aryl ring, or optionally substituted heteroaryl ring comprising at least one N, S, or O atom; wherein Ring C is optionally substituted with —Y.sup.C; [0276] Y.sup.C is —N(R.sup.N1).sub.2, —OR.sup.O1, —SR.sup.S1, each of G.sup.1, G.sup.3, and G.sup.4 is independently selected from the group consisting of O, S, and NR.sup.N3; G.sup.2 is N; [0277] R.sup.3 is hydrogen, halogen, —CN, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or optionally substituted acyl; [0278] L.sup.2 is a bond, optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted carbocyclylene, optionally substituted arylene, optionally substituted heterocyclylene, optionally substituted heteroarylene, optionally substituted acylene, or a combination thereof; [0279] R.sup.1 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, an oxygen protecting group, an amino acid, or a polypeptide; [0280] each instance of R.sup.2 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, a nitrogen protecting group, an amino acid, or a polypeptide; or two R.sup.2 bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; [0281] each instance of R.sup.N1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group; or two R.sup.N1 bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; [0282] R.sup.O1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or an oxygen protecting group; [0283] R.sup.S1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a sulfur protecting group; [0284] each instance of R.sup.N3 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group.

[0285] In certain embodiments, the compound of Formula (IV) is of the formula:

##STR00118##

or a salt, tautomer, or isotopically derivative thereof, wherein: [0286] each instance of R.sup.4 is independently hydrogen, halogen, —CN, —NO.sub.2, —N.sub.3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl optionally substituted sulfonyl, optionally substituted sulfinyl, sulfate, sulfonate, —N(R.sup.N).sub.2, —OR.sup.O, or —SR.sup.S; [0287] each instance of R.sup.N is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group; or two R.sup.N bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; [0288] each instance of R.sup.O is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or an oxygen protecting group; [0289] each instance of R.sup.S is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a sulfur protecting group; and [0290] m is 0, 1, 2, 3, or 4.

[0291] In certain embodiments, the compound of Formula (IV) is of one of the following formulae:

##STR00119##

or a salt, tautomer, or isotopically derivative thereof

Ring A and Y.SUP.A

[0292] As defined herein, Ring A an optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl ring comprising at least one double bond in conjugation with ═Y.sup.A and the group:

##STR00120##

In certain embodiments, Ring A is an optionally substituted carbocyclic ring. In certain embodiments, Ring A is an optionally substituted heterocyclic ring. In certain embodiments, Ring A is an optionally substituted C.sub.6 carbocyclic ring. In certain embodiments, Ring A is an optionally substituted 6-membered heterocyclic ring. In certain embodiment, Ring A is an optionally substituted cyclohexadienyl ring. In certain embodiment, Ring A is an unsubstituted cyclohexadienyl ring.

[0293] In certain embodiments, Ring A is of the formula:

##STR00121##

In certain embodiments, Ring A is of the formula:

##STR00122##

[0294] As defined herein, each of X.sup.1, X.sup.2, X.sup.3, and X.sup.4 are independently N or CR.sup.4. In certain embodiments, X.sup.1 is N. In certain embodiments, X.sup.1 is CR.sup.4. In certain embodiments, X.sup.1 is CH. In certain embodiments, X.sup.2 is N. In certain embodiments, X.sup.2 is CR.sup.4. In certain embodiments, X.sup.2 is CH. In certain embodiments, X.sup.3 is N. In certain embodiments, X.sup.3 is CR.sup.4. In certain embodiments, X.sup.3 is CH. In certain embodiments, X.sup.4 is N. In certain embodiments, X.sup.4 is CR.sup.4. In certain embodiments, X.sup.4 is CH. In certain embodiments, X.sup.1, X.sup.2, X.sup.3, and X.sup.4 are each CR.sup.4. In certain embodiments, X.sup.1, X.sup.2, X.sup.3, and X.sup.4 are each CH.

[0295] In certain embodiments, Ring A is of the formula:

##STR00123##

In certain embodiments, Ring A is of the formula:

##STR00124##

In certain embodiments, Ring A is of the formula:

##STR00125##

In certain embodiments, Ring A is of the formula:

##STR00126##

[0296] As defined herein, ═Y.sup.A is ═N.sup.+(R.sup.N1).sub.2, ═O.sup.+R.sup.O1, ═S.sup.+R.sup.S1, ═NR.sup.N1, ═O, or ═S. In certain embodiments, ═Y.sup.A is ═N.sup.+(R.sup.N1).sub.2. In certain embodiments, ═Y.sup.A is ═N.sup.+(Me).sub.2. In certain embodiments, ═Y.sup.A is ═NH.sub.2+. In certain embodiments, ═Y.sup.A is ═O.sup.+R.sup.O1. In certain embodiments, ═Y.sup.A is ═O.sup.+Me. In certain embodiments, ═Y.sup.A is ═OH.sup.+. In certain embodiments, ═Y.sup.A is ═O. In certain embodiments, ═Y.sup.A is ═S.sup.+R.sup.S1. In certain embodiments, ═Y.sup.A is ═S.sup.+Me. In certain embodiments, ═Y.sup.A is ═SH.sup.+. In certain embodiments, ═Y.sup.A is ═S.

[0297] In certain embodiments, the group

##STR00127##

is of the formula:

##STR00128##

In certain embodiments, the group is of the formula:

##STR00129##

In certain embodiments, the group is of the formula:

##STR00130##

In certain embodiments, the group is of the formula:

##STR00131##

[0298] In certain embodiments, the group is of the formula:

##STR00132##

In certain embodiments, the group is of the formula:

##STR00133##

Ring B and R.SUP.B

[0299] As defined herein, Ring B is optionally substituted aryl or optionally substituted heteroaryl. In certain embodiments, Ring B is optionally substituted aryl. In certain embodiments, Ring B is optionally substituted heteroaryl. In certain embodiments, Ring B is optionally substituted phenyl. In certain embodiments, Ring B is optionally substituted 6-membered heteroaryl. In certain embodiments, Ring is unsubstituted phenyl.

[0300] In certain embodiments, Ring B is of the formula:

##STR00134##

In certain embodiments, Ring B is of the formula:

##STR00135##

In certain embodiments, Ring B is of the formula:

##STR00136##

In certain embodiments, Ring B is of the formula:

##STR00137##

[0301] As defined herein, Y.sup.B is —N(R.sup.N1).sub.2, —OR.sup.O1, or —SR.sup.S1, In certain embodiments, Y.sup.B is —N(R.sup.N1).sub.2, In certain embodiments, Y.sup.B is —N(Me).sub.2. In certain embodiments, Y.sup.B is —NH.sub.2. In certain embodiments, Y.sup.B is —OR.sup.O1. In certain embodiments, Y.sup.B is —OMe. In certain embodiments, Y.sup.B is —OH. In certain embodiments, Y.sup.B is —SR.sup.S1. In certain embodiments, Y.sup.B is —SMe. In certain embodiments, Y.sup.B is —SH.

[0302] In certain embodiments, the group of the formula:

##STR00138##

is of the formula:

##STR00139##

In certain embodiments, the group is of the formula:

##STR00140##

In certain embodiments, the group is of the formula:

##STR00141##

In certain embodiments, the group is of the formula:

##STR00142##

[0303] In certain embodiments, the group is of the formula:

##STR00143##

In certain embodiments, the group is of the formula:

##STR00144##

In certain embodiments, the group is of the formula:

##STR00145##

[0304] In certain embodiments, Ring B is optionally substituted naphthalene. In certain embodiments, Ring B is unsubstituted naphthalene. In certain embodiments, the group

##STR00146##

is of the formula:

##STR00147##

In certain embodiments, the group

##STR00148##

is of the formula:

##STR00149##

In certain embodiments, the group

##STR00150##

is of the formula:

##STR00151##

In certain embodiments, the group

##STR00152##

is of the formula:

##STR00153##

[0305] As defined herein, p is 0, 1, 2, 3, 4, 5, or 6. In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3. In certain embodiments, p is 4. In certain embodiments, p is 5. In certain embodiments, p is 6.

Ring C and Y.SUP.C

[0306] In certain embodiments, Ring C is an optionally substituted heterocyclic or heteroaryl ring comprising at least one N, S, or O atom; wherein the heterocyclic or heteroaryl ring is in conjugation with the group:

##STR00154##

[0307] In certain embodiments, Ring C is an optionally substituted carbocyclic ring. In certain embodiments, Ring C is an optionally substituted heterocyclic ring. In certain embodiments, Ring C is an optionally substituted C.sub.6 carbocyclic ring. In certain embodiments, Ring C is an optionally substituted 6-membered heterocyclic ring. In certain embodiment, Ring C is an optionally substituted cyclohexadienyl ring. In certain embodiment, Ring C is an unsubstituted cyclohexadienyl ring.

[0308] In certain embodiments, Ring C is of the formula:

##STR00155##

In certain embodiments, Ring C is of the formula:

##STR00156##

[0309] In certain embodiments, Ring C is of the formula:

##STR00157##

In certain embodiments, Ring C is of the formula:

##STR00158##

[0310] As defined herein, each of X.sup.1, X.sup.2, X.sup.3, and X.sup.4 are independently N or CR.sup.4. In certain embodiments, X.sup.1 is N. In certain embodiments, X.sup.1 is CR.sup.4. In certain embodiments, X.sup.1 is CH. In certain embodiments, X.sup.2 is N. In certain embodiments, X.sup.2 is CR.sup.4. In certain embodiments, X.sup.2 is CH. In certain embodiments, X.sup.3 is N. In certain embodiments, X.sup.3 is CR.sup.4. In certain embodiments, X.sup.3 is CH. In certain embodiments, X.sup.4 is N. In certain embodiments, X.sup.4 is CR.sup.4. In certain embodiments, X.sup.4 is CH. In certain embodiments, X.sup.1, X.sup.2, X.sup.3, and X.sup.4 are each CR.sup.4. In certain embodiments, X.sup.1, X.sup.2, X.sup.3, and X.sup.4 are each CH.

[0311] In certain embodiments, Ring C is of the formula:

##STR00159##

In certain embodiments, Ring C is of the formula:

##STR00160##

In certain embodiments, Ring C is of the formula:

##STR00161##

In certain embodiments, Ring C is of the formula:

##STR00162##

[0312] In certain embodiments, Ring C is of the formula:

##STR00163##

In certain embodiments, Ring C is of the formula:

##STR00164##

In certain embodiments, Ring C is of the formula:

##STR00165##

In certain embodiments, Ring C is of the formula:

##STR00166##

[0313] As defined herein, custom-character Y.sup.C is ═N.sup.+(R.sup.N1).sub.2, ═O.sup.+R.sup.O1, ═S.sup.+R.sup.S1, —N(R.sup.N1).sub.2, —OR.sup.O1, —SR.sup.S1 ═NR.sup.N1, ═O, or ═S. In certain embodiments, ═Y.sup.C is ═N.sup.+(R.sup.N1).sub.2. In certain embodiments, Y.sup.C is ═N.sup.+(Me).sub.2. In certain embodiments, custom-character Y.sup.C is ═NH.sub.2+. In certain embodiments, Y.sup.C is ═O.sup.+R.sup.O1. In certain embodiments, Y.sup.C is ═O.sup.+Me. In certain embodiments, Y.sup.C is ═OH.sup.+. In certain embodiments, Y.sup.C is ═O. In certain embodiments, Y.sup.C is ═S.sup.+R.sup.S1. In certain embodiments, custom-character Y.sup.C is ═S. In certain embodiments, Y.sup.C is ═S.sup.+Me. In certain embodiments, Y.sup.C is —SH.

[0314] In certain embodiments, the group

##STR00167##

is of the formula:

##STR00168##

In certain embodiments, the group is of the formula:

##STR00169##

In certain embodiments, the group is of the formula:

##STR00170##

In certain embodiments, the group is of the formula:

##STR00171##

[0315] In certain embodiments, the group

##STR00172##

is of the formula:

##STR00173##

In certain embodiments, the group is of the formula:

##STR00174##

In certain embodiments, the group is of the formula:

##STR00175##

In certain embodiments, the group is of the formula:

##STR00176##

[0316] In certain embodiments, Ring C is optionally substituted naphthalene. In certain embodiments, Ring C is unsubstituted naphthalene. In certain embodiments, the group

##STR00177##

is of the formula:

##STR00178##

In certain embodiments, the group

##STR00179##

is of the formula:

##STR00180##

In certain embodiments, the group

##STR00181##

is of the formula:

##STR00182##

In certain embodiments, the group

##STR00183##

is of the formula:

##STR00184##

[0317] As defined herein, p is 0, 1, 2, 3, 4, 5, or 6. In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3. In certain embodiments, p is 4. In certain embodiments, p is 5. In certain embodiments, p is 6.

[0318] In certain embodiments, Ring C is an optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl ring substituted with ═Y.sup.C and comprising at least one double bond in conjugation with ═Y.sup.C and the group:

##STR00185##

In certain embodiments, Ring C is an optionally substituted 5-membered heterocyclic ring. In certain embodiments, Ring C is an optionally substituted 6-membered heterocyclic ring.

[0319] In certain embodiments, Ring is of the formula:

##STR00186##

As defined herein, each of G.sup.1, G.sup.2, G.sup.3, and G.sup.4 is independently selected from the group consisting of O, S, and NR.sup.N3. In certain embodiments, G.sup.1 is O. In certain embodiments, G.sup.1 is S. In certain embodiments, G.sup.1 is NR.sup.N3. In certain embodiments, G.sup.1 is NH. In certain embodiments, G.sup.2 is 0. In certain embodiments, G.sup.2 is S. In certain embodiments, G.sup.2 is NR.sup.N3. In certain embodiments, G.sup.2 is NH. In certain embodiments, G.sup.3 is O. In certain embodiments, G.sup.3 is S. In certain embodiments, G.sup.3 is NR.sup.N3. In certain embodiments, G.sup.3 is NH. In certain embodiments, G.sup.4 is O. In certain embodiments, G.sup.4 is S. In certain embodiments, G.sup.4 is NR.sup.N3. In certain embodiments, G.sup.4 is NH. In certain embodiments, G.sup.1 is S; G.sup.2 is NR.sup.N3; G.sup.3 is S; and G.sup.4 is O. In certain embodiments, G.sup.1 is S; G.sup.2 is NH; G.sup.3 is S; and G.sup.4 is O.

[0320] As defined herein, each instance of R.sup.N3 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group. In certain embodiments, at least one instance of R.sup.N3 is hydrogen. In certain embodiments, at least one instance of R.sup.N3 is optionally substituted alkyl. In certain embodiments, at least one instance of R.sup.N3 is optionally substituted alkenyl. In certain embodiments, at least one instance of R.sup.N3 is optionally substituted alkynyl. In certain embodiments, at least one instance of R.sup.N3 is optionally substituted aryl. In certain embodiments, at least one instance of R.sup.N3 is optionally substituted heteroaryl. In certain embodiments, at least one instance of R.sup.N3 is optionally substituted carbocyclyl. In certain embodiments, at least one instance of R.sup.N3 is optionally substituted heterocyclyl. In certain embodiments, at least one instance of R.sup.N3 is optionally substituted acyl. In certain embodiments, at least one instance of R.sup.N3 is a nitrogen protecting group. In certain embodiments, each instance of R.sup.N3 is hydrogen.

[0321] In certain embodiments, Ring C is an optionally substituted aryl ring, or optionally substituted heteroaryl ring comprising at least one N, S, or O atom; wherein Ring C is optionally substituted with —Y.sup.C. In certain embodiments, Ring C is substituted with —Y.sup.C. In certain embodiments, Ring C is an optionally substituted aryl ring substituted with —Y.sup.C.

Ring D and Y

[0322] As defined herein, Ring D is optionally substituted aryl or optionally substituted heteroaryl. In certain embodiments, Ring D is optionally substituted aryl. In certain embodiments, Ring D is optionally substituted heteroaryl. In certain embodiments, Ring D is optionally substituted phenyl. In certain embodiments, Ring D is optionally substituted 6-membered heteroaryl. In certain embodiments, Ring is unsubstituted phenyl.

[0323] In certain embodiments, Ring D is of the formula:

##STR00187##

In certain embodiments, Ring D is of the formula:

##STR00188##

In certain embodiments, Ring D is of the formula:

##STR00189##

In certain embodiments, Ring D is of the formula:

##STR00190##

As defined herein, Y is a bond, —O—, —NR.sup.N2—, or —S—. In certain embodiments, Y is —O—. In certain embodiments, Y is —NR.sup.N2—. In certain embodiments, Y is —NH—. In certain embodiments, Y is —S—. In certain embodiments, Y is a bond.

[0324] As defined herein, R.sup.N2 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group. In certain embodiments, R.sup.N2 is hydrogen. In certain embodiments, R.sup.N2 is optionally substituted alkyl. In certain embodiments, R.sup.N2 is optionally substituted alkenyl. In certain embodiments, R.sup.N2 is optionally substituted alkynyl. In certain embodiments, R.sup.N2 is optionally substituted aryl. In certain embodiments, R.sup.N2 is optionally substituted heteroaryl. In certain embodiments, R.sup.N2 is optionally substituted carbocyclyl. In certain embodiments, R.sup.N2 is optionally substituted heterocyclyl. In certain embodiments, R.sup.N2 is optionally substituted acyl. In certain embodiments, R.sup.N2 is a nitrogen protecting group. In certain embodiments, R.sup.N2 is hydrogen.

R.SUP.4 .and m

[0325] As defined herein, each instance of R.sup.4 is independently hydrogen, halogen, —CN, —NO.sub.2, —N.sub.3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, sulfate, sulfonate, —N(R.sup.N).sub.2, —OR.sup.O, or —SR.sup.S. In certain embodiments, at least one instance of R.sup.4 is hydrogen. In certain embodiments, at least one instance of R.sup.4 is halogen (i.e., —Cl, —Br, —I, and —F). In certain embodiments, at least one instance of R.sup.4 is —CN. In certain embodiments, at least one instance of R.sup.4 is —NO.sub.2. In certain embodiments, at least one instance of R.sup.4 is —N.sub.3. In certain embodiments, at least one instance of R.sup.4 is optionally substituted alkyl. In certain embodiments, at least one instance of R.sup.4 is optionally substituted alkenyl. In certain embodiments, at least one instance of R.sup.4 is optionally substituted alkynyl. In certain embodiments, at least one instance of R.sup.4 is optionally substituted aryl. In certain embodiments, at least one instance of R.sup.4 is optionally substituted heteroaryl. In certain embodiments, at least one instance of R.sup.4 is optionally substituted carbocyclyl. In certain embodiments, at least one instance of R.sup.4 is optionally substituted heterocyclyl. In certain embodiments, at least one instance of R.sup.4 is optionally substituted acyl. In certain embodiments, at least one instance of R.sup.4 is —N(R.sup.N).sub.2. In certain embodiments, at least one instance of R.sup.4 is —OR.sup.O. In certain embodiments, at least one instance of R.sup.4 is —SR.sup.S. In certain embodiments, at least one instance of R.sup.4 is optionally substituted sulfinyl. In certain embodiments, at least one instance of R.sup.4 is optionally substituted sulfonyl. In certain embodiments, at least one instance of R.sup.4 is optionally substituted sulfinate. In certain embodiments, at least one instance of R.sup.4 is optionally substituted sulfonate.

[0326] In certain embodiments, each instance of R.sup.4 is hydrogen.

[0327] As defined herein, each instance of m is independently 0, 1, 2, 3, or 4. In certain embodiments, at least one instance of m is 0. In certain embodiments, at least one instance of m is 1. In certain embodiments, at least one instance of m is 2. In certain embodiments, at least one instance of m is 3. In certain embodiments, at least one instance of m is 4. In certain embodiments, each instance of m is 0.

R.sup.N1, R.sup.O1, R.sup.S1

[0328] As defined herein, each instance of R.sup.N1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group; or two R.sup.N1 bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl. In certain embodiments, at least one instance of R.sup.N1 is hydrogen. In certain embodiments, at least one instance of R.sup.N1 is optionally substituted alkyl. In certain embodiments, at least one instance of R.sup.N1 is optionally substituted alkenyl. In certain embodiments, at least one instance of R.sup.N1 is optionally substituted alkynyl. In certain embodiments, at least one instance of R.sup.N1 is optionally substituted aryl. In certain embodiments, at least one instance of R.sup.N1 is optionally substituted heteroaryl. In certain embodiments, at least one instance of R.sup.N1 is optionally substituted carbocyclyl. In certain embodiments, at least one instance of R.sup.N1 is optionally substituted heterocyclyl. In certain embodiments, at least one instance of R.sup.N1 is optionally substituted acyl. In certain embodiments, at least one instance of R.sup.N1 is a nitrogen protecting group. In certain embodiments, two R.sup.N1 bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl. In certain embodiments, two R.sup.N1 bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heteroaryl. In certain embodiments, at least one instance of R.sup.N1 is optionally substituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.N1 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.N1 is optionally substituted C.sub.1-3 alkyl. In certain embodiments, at least one instance of R.sup.N1 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.N1 is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl. In certain embodiments, at least one instance of R.sup.N1 is methyl. In certain embodiments, each instance of R.sup.N1 is methyl. In certain embodiments, each instance of R.sup.N1 is hydrogen.

[0329] In certain embodiments, a group of the formula —N(R.sup.N1).sub.2 is of the formula:

##STR00191##

In certain embodiments, a group of the formula —N(R.sup.N1).sub.2 is of the formula:

##STR00192##

In certain embodiments, a group of the formula —N(R.sup.N1).sub.2 is of the formula:

##STR00193##

In certain embodiments, a group of the formula —N(R.sup.N1).sub.2 is of the formula:

##STR00194##

In certain embodiments, a group of the formula —N(R.sup.N1).sub.2 is of the formula:

##STR00195##

In certain embodiments, a group of the formula —N(R.sup.N1).sub.2 is of the formula:

##STR00196##

[0330] As defined herein, each instance of R.sup.O1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or an oxygen protecting group. In certain embodiments, at least one instance of R.sup.O1 is hydrogen. In certain embodiments, at least one instance of R.sup.O1 is optionally substituted alkyl. In certain embodiments, at least one instance of R.sup.O1 is optionally substituted alkenyl. In certain embodiments, at least one instance of R.sup.O1 is optionally substituted alkynyl. In certain embodiments, at least one instance of R.sup.O1 is optionally substituted aryl. In certain embodiments, at least one instance of R.sup.O1 is optionally substituted heteroaryl. In certain embodiments, at least one instance of R.sup.O1 is optionally substituted carbocyclyl. In certain embodiments, at least one instance of R.sup.O1 is optionally substituted heterocyclyl. In certain embodiments, at least one instance of R.sup.O1 is optionally substituted acyl. In certain embodiments, at least one instance of R.sup.O1 is an oxygen protecting group. In certain embodiments, at least one instance of R.sup.O1 is optionally substituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.O1 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.O1 is optionally substituted C.sub.1-3 alkyl. In certain embodiments, at least one instance of R.sup.O1 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.O1 is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl. In certain embodiments, at least one instance of R.sup.O1 is methyl. In certain embodiments, each instance of R.sup.O1 is methyl. In certain embodiments, each instance of R.sup.O1 is hydrogen.

[0331] As defined herein, each instance of R.sup.S1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a sulfur protecting group. In certain embodiments, at least one instance of R.sup.S1 is hydrogen. In certain embodiments, at least one instance of R.sup.S1 is optionally substituted alkyl. In certain embodiments, at least one instance of R.sup.S1 is optionally substituted alkenyl. In certain embodiments, at least one instance of R.sup.S1 is optionally substituted alkynyl. In certain embodiments, at least one instance of R.sup.S1 is optionally substituted aryl. In certain embodiments, at least one instance of R.sup.S1 is optionally substituted heteroaryl. In certain embodiments, at least one instance of R.sup.S1 is optionally substituted carbocyclyl. In certain embodiments, at least one instance of R.sup.S1 is optionally substituted heterocyclyl. In certain embodiments, at least one instance of R.sup.S1 is optionally substituted acyl. In certain embodiments, at least one instance of R.sup.S1 is an oxygen protecting group. In certain embodiments, at least one instance of R.sup.S1 is optionally substituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.S1 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.S1 is optionally substituted C.sub.1-3 alkyl. In certain embodiments, at least one instance of R.sup.S1 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.S1 is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl. In certain embodiments, at least one instance of R.sup.S1 is methyl. In certain embodiments, each instance of R.sup.S1 is methyl. In certain embodiments, each instance of R.sup.S1 is hydrogen.

[0332] As generally defined herein, each instance of R.sup.C is independently hydrogen, halogen, —CN, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or optionally substituted acyl, optionally wherein two R.sup.C on the same carbon atom are joined together with the intervening atoms to form optionally substituted carbocyclyl or optionally substituted heterocyclyl. In certain embodiments, each R.sup.C is hydrogen. In certain embodiments, each R.sup.C is optionally substituted alkyl.

R.sup.3 and custom-character

[0333] As defined herein, R.sup.3 is hydrogen, ═NR.sup.NX, —N—R.sup.NX, ═S, —S—, ═O, —O—, ═C(R.sup.C).sub.2, halogen, —CN, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or optionally substituted acyl. In certain embodiments, R.sup.3 is hydrogen. In certain embodiments, R.sup.3 is ═O. In certain embodiments, R.sup.3 is halogen. In certain embodiments, R.sup.3 is —CN. In certain embodiments, R.sup.3 is optionally substituted alkyl. In certain embodiments, R.sup.3 is optionally substituted alkenyl. In certain embodiments, R.sup.3 is optionally substituted alkynyl. In certain embodiments, R.sup.3 is optionally substituted aryl. In certain embodiments, R.sup.3 is optionally substituted heteroaryl. In certain embodiments, R.sup.3 is optionally substituted carbocyclyl. In certain embodiments, R.sup.3 is optionally substituted heterocyclyl. In certain embodiments, R.sup.3 is or optionally substituted acyl. In certain embodiments, R.sup.3 is ═C(R.sup.C).sub.2. In certain embodiments, R.sup.3 is ═CH.sub.2. In certain embodiments, R.sup.3 is ═NR.sup.NX. In certain embodiments, R.sup.3 is —N—R.sup.NX. In certain embodiments, R.sup.3 is ═S. In certain embodiments, R.sup.3 is ═NR.sup.NX—S.sup.−.

[0334] As defined herein, custom-character is a single or double bond; provided that when is a single bond, R.sup.3 is ═NR.sup.NX, ═S, ═O or ═C(R.sup.C).sub.2; and when is a double bond, R.sup.3 is not ═NR.sup.NX, ═O or ═C(R.sup.C).sub.2. In certain embodiments, is a double bond; and R.sup.3 is hydrogen. In certain embodiments, custom-character is a single bond; and R.sup.3 is ═O. In certain embodiments, is a single bond; and R.sup.3 is ═C(R.sup.C).sub.2. In certain embodiments, is a single bond; and R.sup.3 is ═CH.sub.2. In certain embodiments, is a single bond; and R.sup.3 is ═C(CN).sub.2. In certain embodiments, custom-character is a single bond; and R.sup.3 is ═C(CN)(CO.sub.2H). In certain embodiments, is a single bond; and R.sup.3 is ═NR.sup.NX. In certain embodiments, is a single bond; and R.sup.3 is ═NH. In certain embodiments, is a single bond; and R.sup.3 is ═S.

[0335] As defined herein, R.sup.NX is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group. In certain embodiments, R.sup.NX is hydrogen. In certain embodiments, R.sup.NX is optionally substituted alkyl. In certain embodiments, R.sup.NX is optionally substituted alkenyl. In certain embodiments, R.sup.NX is optionally substituted alkynyl. In certain embodiments, R.sup.NX is optionally substituted aryl. In certain embodiments, R.sup.NX is optionally substituted heteroaryl. In certain embodiments, R.sup.NX is optionally substituted carbocyclyl. In certain embodiments, R.sup.NX is optionally substituted heterocyclyl. In certain embodiments, R.sup.NX is optionally substituted acyl. In certain embodiments, R.sup.NX is a nitrogen protecting group.

L.sup.1 and L.sup.2

[0336] As defined herein, L.sup.1 is a bond, optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkynylene, optionally substituted carbocyclylene, optionally substituted arylene, optionally substituted heterocyclylene optionally substituted heteroarylene, optionally substituted acylene, or a combination thereof. In certain embodiments, L.sup.1 is a bond. In certain embodiments, L.sup.1 comprises optionally substituted alkylene. In certain embodiments, L.sup.1 comprises optionally substituted heteroalkylene. In certain embodiments, L.sup.1 comprises optionally substituted alkenylene. In certain embodiments, L.sup.1 comprises optionally substituted alkynylene. In certain embodiments, L.sup.1 comprises optionally substituted carbocyclylene. In certain embodiments, L.sup.1 comprises optionally substituted arylene. In certain embodiments, L.sup.1 comprises optionally substituted heterocyclylene. In certain embodiments, L.sup.1 comprises optionally substituted heteroarylene. In certain embodiments, L.sup.1 comprises optionally substituted acylene. In certain embodiments, L.sup.1 is optionally substituted heteroalkenylene. In certain embodiments, L.sup.1 is optionally substituted heteroalkynylene.

[0337] In certain embodiments, LV is optionally substituted alkylene. In certain embodiments, L.sup.1 is optionally substituted C.sub.1-6 alkylene. In certain embodiments, L.sup.1 is unsubstituted C.sub.1-6 alkylene. In certain embodiments, L.sup.1 is optionally substituted C.sub.1-3 alkylene. In certain embodiments, L.sup.1 is unsubstituted C.sub.1-6 alkylene. In certain embodiments, L.sup.1 is of the formula:

##STR00197##

wherein n is an integer from 1-6, inclusive. As defined herein, n is an integer from 1-6, inclusive. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4. In certain embodiments, n is 5. In certain embodiments, n is 6.

[0338] In certain embodiments, L.sup.1 is of one of the following formulae:

##STR00198##

[0339] In certain embodiments, L.sup.1 is of the formula:

##STR00199##

In certain embodiments, L.sup.1 is of the formula:

##STR00200##

In certain embodiments, L.sup.1 is of the formula:

##STR00201##

[0340] In certain embodiments, L.sup.1 is of the formula:

##STR00202##

In certain embodiments, L.sup.1 is of the formula:

##STR00203##

In certain embodiments, L.sup.1 is of the formula:

##STR00204##

In certain embodiments, L.sup.1 is of the formula:

##STR00205##

In certain embodiments, L.sup.1 is of the formula:

##STR00206##

[0341] As defined herein, L.sup.2 is a bond, optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted carbocyclylene, optionally substituted arylene, optionally substituted heterocyclylene optionally substituted heteroarylene, optionally substituted acylene, or a combination thereof. In certain embodiments, L.sup.2 is a bond. In certain embodiments, L.sup.2 comprises optionally substituted alkylene. In certain embodiments, L.sup.2 comprises optionally substituted heteroalkylene. In certain embodiments, L.sup.2 comprises optionally substituted alkenylene. In certain embodiments, L.sup.2 comprises optionally substituted alkynylene. In certain embodiments, L.sup.2 comprises optionally substituted carbocyclylene. In certain embodiments, L.sup.2 comprises optionally substituted arylene. In certain embodiments, L.sup.2 comprises optionally substituted heterocyclylene. In certain embodiments, L.sup.2 comprises optionally substituted heteroarylene. In certain embodiments, L.sup.2 comprises optionally substituted acylene.

[0342] In certain embodiments, L.sup.2 is optionally substituted alkylene. In certain embodiments, L.sup.2 is optionally substituted C.sub.1-6 alkylene. In certain embodiments, L.sup.2 is unsubstituted C.sub.1-6 alkylene. In certain embodiments, L.sup.2 is optionally substituted C.sub.1-3 alkylene. In certain embodiments, L.sup.2 is unsubstituted C.sub.1-6 alkylene. In certain embodiments, L.sup.2 is of the formula:

##STR00207##

##STR00208##

[0343] In certain embodiments, L.sup.2 is optionally substituted alkylene. In certain embodiments, L.sup.2 is optionally substituted C.sub.1-6 alkylene. In certain embodiments, L.sup.2 is unsubstituted C.sub.1-6 alkylene. In certain embodiments, L.sup.2 is optionally substituted C.sub.1-3 alkylene. In certain embodiments, L.sup.2 is unsubstituted C.sub.1-6 alkylene.

[0344] In certain embodiments, L.sup.2 is of the following formula:

##STR00209##

In certain embodiments, L.sup.2 is of the following formula:

##STR00210##

In certain embodiments, L.sup.2 is of the following formula:

##STR00211##

In certain embodiments, L.sup.2 is of the following formula:

##STR00212##

In certain embodiments, L.sup.2 is of the following formula:

##STR00213##

[0345] As defined herein, s is 0, 1, 2, 3, 4, 5, or 6. In certain embodiments, s is 0. In certain embodiments, s is 1. In certain embodiments, s is 2. In certain embodiments, s is 3. In certain embodiments, s is 4. In certain embodiments, s is 5. In certain embodiments, s is 6.

R.sup.1 and R.sup.2

[0346] As defined herein, R.sup.1 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, an oxygen protecting group, an amino acid, or a polypeptide. In certain embodiments, R.sup.1 is hydrogen. In certain embodiments, R.sup.1 is optionally substituted alkyl. In certain embodiments, R.sup.1 is optionally substituted alkenyl. In certain embodiments, R.sup.1 is optionally substituted alkynyl. In certain embodiments, R.sup.1 is optionally substituted aryl. In certain embodiments, R.sup.1 is optionally substituted heteroaryl. In certain embodiments, R.sup.1 is optionally substituted carbocyclyl. In certain embodiments, R.sup.1 is optionally substituted heterocyclyl. In certain embodiments, R.sup.1 is optionally substituted acyl. In certain embodiments, R.sup.1 is an oxygen protecting group. In certain embodiments, R.sup.1 is an amino acid. In certain embodiments, R.sup.1 is a polypeptide.

[0347] As defined herein, each instance of R.sup.2 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, a nitrogen protecting group, an amino acid, or a polypeptide; or two R.sup.2 bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl. In certain embodiments, at least one instance of R.sup.2 is hydrogen. In certain embodiments, at least one instance of R.sup.2 is optionally substituted alkyl. In certain embodiments, at least one instance of R.sup.2 is optionally substituted alkenyl. In certain embodiments, at least one instance of R.sup.2 is optionally substituted alkynyl. In certain embodiments, at least one instance of R.sup.2 is optionally substituted aryl. In certain embodiments, at least one instance of R.sup.2 is optionally substituted heteroaryl. In certain embodiments, at least one instance of R.sup.2 is optionally substituted carbocyclyl. In certain embodiments, at least one instance of R.sup.2 is optionally substituted heterocyclyl. In certain embodiments, at least one instance of R.sup.2 is optionally substituted acyl. In certain embodiments, at least one instance of R.sup.2 is a nitrogen protecting group. In certain embodiments, at least one instance of R.sup.2 is an amino acid. In certain embodiments, at least one instance of R.sup.2 is a polypeptide. In certain embodiments, two R.sup.2 bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl. In certain embodiments, two R.sup.2 bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heteroaryl. In certain embodiments, each instance of R.sup.2 is hydrogen.

R.sup.N, R.sup.O, and R.sup.S

[0348] As defined herein, each instance of R.sup.N is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group; or two R.sup.N bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl.

[0349] As defined herein, each instance of R.sup.O is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or an oxygen protecting group.

[0350] As defined herein, each instance of R.sup.S is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a sulfur protecting group.

Methods of Use, Compositions, and Kits

[0351] The compounds described herein (e.g., compounds of Formulae (I), (II), (III), and (IV)) can be used as fluorescent labeling reagents in the fluorescent labeling and imaging of biomolecules and/or cells.

[0352] Provided herein are methods of labeling a biomolecule and/or cell, the method comprising exposing the biomolecule and/or cell to a compound of Formula (I), (II), (III), or (IV), or a salt, tautomer, or isotopically labeled derivative thereof. In certain embodiments, the compound is covalently incorporated into the biomolecule and/or cell (e.g., through enzymatic incorporation, chemical synthesis, ribosomal incorporation). In certain embodiments, the method comprises exposing the biomolecule and/or cell to a compound of Formula (I), (II), (III), or (IV), or a salt, tautomer, or isotopically labeled derivative thereof, in the presence of an enzyme capable of incorporating the compound into the biomolecule and/or cell. In certain embodiments, the compound is covalently incorporated into a biomolecule. In certain embodiments, the biomolecule is in a cell (e.g., in a cell wall, cytoplasm, or nucleus).

[0353] In certain embodiments, the biomolecule is a protein, polypeptide, glycan, peptidoglycan, or nucleic acid. In certain embodiments, biomolecule is a protein. In certain embodiments, the biomolecule is a polypeptide. In certain embodiments, the biomolecule is a glycan. In certain embodiments, the biomolecule is peptidoglycan. In certain embodiments, the biomolecule is a nucleic acid (e.g., oligonucleotide, DNA, RNA, mRNA). In certain embodiments, the biomolecule is an antibody or a fragment thereof. In certain embodiments, the biomolecule is a nanobody.

[0354] In certain embodiments, the biomolecule is in a cell (e.g., in a cell wall). In certain embodiments, the cell is a eukaryotic cell. In certain embodiments, the cell is prokaryotic cell. In certain embodiments, the cell is mammalian cell. In certain embodiments, the cell is a human cell. In certain embodiments, cell is a bacterial cell. In certain embodiments, the cell is a plant cell. In certain embodiments, the biomolecule is peptidoglycan in the wall of a cell. In certain embodiments, the biomolecule is peptidoglycan in the wall of a bacterial cell.

[0355] As described herein, the compound may be incorporated into a biomolecule via enzymatic incorporation. In certain embodiments, the compound is incorporated into a biomolecule (e.g., protein, polypeptide, peptidoglycan) through transpeptidation. Therefore, in certain embodiments, the method of labeling a biomolecule comprises exposing the biomolecule to a compound of Formula (I), (II), (III), or (IV), or a salt, tautomer, or isotopically labeled derivative thereof, in the presence of a transpeptidase. In certain embodiments, a compound described herein is incorporated into peptidoglycan via transpeptidation (e.g., D,D-transpeptidation or L,D-transpeptidation). Therefore, in certain embodiments, the method comprises exposing peptidoglycan to a compound of Formula (I), (II), (III), or (IV), or a salt, tautomer, or isotopically labeled derivative thereof, in the presence of a transpeptidase (e.g., D,D-transpeptidase or L,D-transpeptidase).

[0356] In certain embodiments, a compound described herein (e.g., a compound of Formula (I), (II), (III), or (IV)) is covalently attached to a biomolecule (e.g., protein, polypeptide) or another amino acid via chemical synthesis (e.g., in the presence of a peptide coupling reagent).

[0357] In certain embodiments, the compounds described herein may be conjugated to nucleotides (e.g., nucleotide bases) to form modified nucleotides or oligonucleotides. Examples of amino acid-containing nucleotides include, but are not limited to, Lysidine and other non-standard nucleotides (see, e.g., Tetrahedron Volume 72, Issue 29, 21 Jul. 2016, Pages 4177-4185). For example, conjugating a fluorescent amino acid onto an RNA (e.g., guide RNA) can lead to a fluorogenic readout for association of the RNA and the target.

[0358] In general, the compounds described herein can provide a functional readout, e.g., for protein-protein interactions or protein localization, when the compounds are judicially placed on an enzyme. Additionally, in drug discovery assays, the target protein may include a fluorogenic amino acid. In this instance, screening binding affinity of small molecules to the target protein may have a fluorescent readout.

[0359] After labeling a biomolecule and/or cell with a FgAA compound described herein, the fluorescence of the resulting labeled biomolecule or cell can be observed and/or measured. Therefore, provided herein is a method of detecting a biomolecule and/or cell comprising: [0360] (a) labeling the biomolecule and/or cell via any one of the methods described above; and [0361] (b) measuring or observing the fluorescence of the biomolecule and/or cell.

[0362] Also provided herein are methods of detecting a labeled biomolecule or cell described herein, the methods comprising measuring or observing the fluorescence of the biomolecule and/or cell.

[0363] Also provided herein are compositions comprising an FgAA compound described herein (e.g., a compound of Formula (I), (II), (III), or (IV)). In certain embodiments, a composition will comprise a compound provided herein and a solution or excipient.

[0364] Also provided herein are kits comprising a FgAA compound described herein (e.g., a compound of Formula (I), (II), (III), or (IV)), or a composition thereof. In certain embodiments, a kit will comprise a compound provided herein, or a composition thereof, and optionally one or more chemical reagents or enzymes. In certain embodiments, the kit comprises one or more chemical synthesis reagents (e.g., peptide coupling reagents). In certain embodiments, the kit comprises one or more enzymes (e.g., transpeptidases, e.g., D,D-transpeptidase or L,D-transpeptidase).

Biomolecules and Cells

[0365] Also provided herein are biomolecules comprising a compound of Formula (I), (II), (III), or (IV), or a salt, tautomer, or isotopically labeled derivative thereof (i.e., “labeled biomolecules”). In certain embodiments, the compound is covalently incorporated into (i.e., covalently attached to) the biomolecule. In certain embodiments, the compound is covalently attached to the biomolecule through one or more peptide bonds. In certain embodiments, the compound is covalently attached to the biomolecule through one or more ester linkages. In certain embodiments, the compound is covalently attached to the biomolecule through one or more disulfide bonds. The labeled biomolecule can comprise one or more of the compounds described herein. In certain embodiments, the labeled biomolecule comprises more than one of the compounds described herein.

[0366] In certain embodiments, the biomolecule is a protein, polypeptide, glycan, peptidoglycan, or nucleic acid. In certain embodiments, biomolecule is a protein. In certain embodiments, the biomolecule is a polypeptide. In certain embodiments, the biomolecule is a glycan. In certain embodiments, the biomolecule is peptidoglycan. In certain embodiments, the biomolecule is a nucleic acid. In certain embodiments, the labeled biomolecule is in a cell. In certain embodiments, the labeled biomolecule is in the wall of a cell. In certain embodiments, the labeled biomolecule is in the cytoplasm or nucleus of a cell.

[0367] Also provided herein are cells comprising a compound of Formula (I), (II), (III), or (IV), or a salt, tautomer, or isotopically labeled derivative thereof. In certain embodiments, the compound is covalently incorporated into (i.e., covalently attached to) the cell. In certain embodiments, the compound is in the intracellular fluid of the cell. In certain embodiments, the cell comprises a labeled biomolecule described herein. In certain embodiments, the cell comprises a labeled biomolecule described herein in the wall of the cell. In certain embodiments, the cell comprises a labeled biomolecule is in the cytoplasm or nucleus of a cell.

[0368] In certain embodiments, the cell is a eukaryotic cell. In certain embodiments, the cell is prokaryotic cell. In certain embodiments, the cell is mammalian cell. In certain embodiments, the cell is a human cell. In certain embodiments, cell is a bacterial cell. In certain embodiments, the cell is a plant cell. In certain embodiments, the cell comprises a labeled peptidoglycan. In certain embodiments, the cell comprises a labeled peptidoglycan in the wall of the cell. In certain embodiments, the cell is a bacterial cell comprising a labeled peptidoglycan in the wall of the cell.

EXAMPLES

[0369] These and other aspects of the present invention will be further appreciated upon consideration of the following Examples, which are intended to illustrate certain particular embodiments of the invention but are not intended to limit its scope, as defined by the claims.

[0370] Previously, it has been demonstrated that the bacterial cell wall machinery has an unprecedented, inherent promiscuity to incorporate synthetic D-amino acids with substantial side groups. In comparison, the protein translation machinery has a much narrower tolerance to large synthetic L-amino acids such as non-standard amino acids (nsAAs). Described herein is the design and testing of new fluorogenic amino acids (FgAAs) that are small enough to be tolerated by translation machinery. New fluorogenic amino acids (FgAAs) that are smaller, distinctly colored, significantly more fluorogenic, and harbor different geometries than state-of-the-art FgAAs were prepared (compounds v.2a-e, FIG. 2). These VFgAAs are virtually dark in aqueous buffer, or when incubated with live cells, unless they are in viscous environments, e.g., in glycerol, in the cytoplasm of a cell, or covalently linked to bacterial cell walls (FIGS. 3B-3C).

[0371] The compounds described herein can replace fluorescent proteins (FPs) in many bimolecular and cellular labeling applications. In certain embodiments, the compounds described herein are advantageous because: (1) they are orders of magnitude smaller than FPs resulting in minimal perturbation to tagged proteins (see, e.g., FIG. 1); and/or (2) the compounds are rapidly visible upon biomolecule incorporation as they do not require maturation nor oxygen to turn on. In other embodiments, incorporating the compounds into antibodies or nanobodies can help evaluate antibodies against different antigens (i.e., the tighter such an antibody binds to its target, the brighter the labeled biomolecule or cell).

[0372] Compound v.2e, the smallest far-red fluorescing FgAA now known, has a counter-intuitive fluorogenic compound design. Based on the structure of the red fluorescent dye tetramethylrhodamine (TAMRA), this new amino acid reduces TAMRA to a bare minimum scaffold. This scaffold is a small structural mimic of known nsAAs such as BpA (See FIG. 2), but is also fluorogenic. TAMRA without the two carbonyl groups is still fluorescent. However, absent its oxygen bridge, the intramolecular rotations of the now free aromatic rings turn the fluorescence off in environments that are not spatially constrained (See, e.g., FIG. 3). This molecule resembles the dye Malachite Green (MG). This sizable dye is fluorogenic in that it fluoresces only when its intramolecular rotations are restricted in viscous environments or when bound to macromolecules. Shedding the phenyl and the tetramethyl groups of MG are counter-intuitive steps. However, this attempt not only made these molecules much smaller; but it also rendered these fluorophores functionalizable through their now free amines. Indeed, functionalization of these molecules to compounds v.2b and v.2e did not impact the fluorogenicity of these molecules and resulted in the smallest far-red fluorescing FgAAs currently known (See, e.g., FIG. 3B). Significantly, compound v.2e (and its derivative v.2d) are structurally similar to BpA (See, e.g., FIG. 2), an nsAA that can efficiently be encoded into proteins. Finally, v.2d in D-chirality also allowed wash-free visualization of PG biosynthesis indicating that these new FgAAs behave as expected in live bacteria (See, e.g., FIG. 3C).

Synthesis of FgAAs

[0373] ##STR00214##

[0374] To a stirring solution of the protected amino acid (circa 1 gram) in THF (20 mL solvent) at −78° C. was added Grignard reagent (25 mL, 0.5 M). 20 mL of dioxane was added and the cooling bath was removed to allow the reaction to warm to room temperature and continue for 4 hours. The reaction was stopped by pouring into mildly acid water (circa pH 3, HCl). The compound—which stayed in the water at acidic and basic pHs was washed with ethyl acetate and DCM at both acidities. The compound was then extracted out of the acidified solution using several portions of IPA:EtOAc:AcOH (1:4:1%). The compound was washed with brine and dried over MgS04. Upon concentration the product solidifies to a greenish/white flacks. Recrystallizing out of DCM provides the pure product in good yield (circa 700 mg).

##STR00215##

[0375] To Michler's ketone in IPA was added a NaBH.sub.4 (gram pellet). The reaction was heated to reflux and allowed to continue for 6 hours. The product was washed with NaOH (aq), extracted with EtOAc washed with brine and dried over Na.sub.2SO.sub.4. A portion of the alcohol product was diluted with DCM (clear and colorless resultant solution) and several drops of BH.sub.4F (aq) was added and the resulting deep blue solution was mixed vigorously. To this was added Boc-Phe(4-aminio)OH. The solution turned clear and almost colorless and DDQ was added in one portion and mixed vigorously. The reaction solution was diluted with basic was washed with EtOAc and acidified, extracted into EtOAc, washed with brine and dried over Na.sub.2SO.sub.4. The crude product was loaded onto a silica column and a gradient of hexane to 100%. Reverse phase HPLC-MS showed a mostly pure peak for 531.1 DA at 9.29 minutes. This purified compound was concentrated in vacuo and stirred in 1:1 DCM:TFA for 2 hours at 0 degrees to remove the Boc protecting group. The isolated compound was run on LCMS which showed a mostly pure compound (431.3 Da, RT=5.98 min).

Equivalents and Scope

[0376] Text here. In the claims articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

[0377] Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0378] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the invention can be excluded from any claim, for any reason, whether or not related to the existence of prior art.

[0379] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims.

FLUOROGENIC AMINO ACIDS

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Abstract

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Description