The present invention relates to methods and reagents for use in site-selective modification of proteins having lysine residues with functionalized peptides using a chemoenzymatic microbial transglutaminase-mediated reaction. The functionalized proteins may be used for study or therapeutic uses.

The present invention relates to methods and reagents for use in site-selective modification of proteins having lysine residues with functionalized peptides using a chemoenzymatic microbial transglutaminase-mediated reaction. The functionalized proteins may be used for study or therapeutic uses.

The present invention concerns a novel method for synthesising diazirines, that may or may not be enriched in nitro-gen-15, from amino acids or imines, via a one-pot synthesis method, comprising the reaction of the starting amino acid or imine with ammonia, which may or may not be enriched in nitrogen-15, and a hypervalent iodine oxidant. The present invention also relates to a method for synthesising ammonia enriched in nitrogen-15. The invention also concerns certain diazirines of formula (I) likely to be obtained by the claimed synthesis method, and also refers to the .sup.15N.sub.2-diazirines of formula (I′). The claimed diazirines can be used in photoaffinity labelling. The .sup.15N.sub.2-diazirines can also be used in hyperpolarisation, in particular in the medical imaging field.

The present invention concerns a novel method for synthesising diazirines, that may or may not be enriched in nitro-gen-15, from amino acids or imines, via a one-pot synthesis method, comprising the reaction of the starting amino acid or imine with ammonia, which may or may not be enriched in nitrogen-15, and a hypervalent iodine oxidant. The present invention also relates to a method for synthesising ammonia enriched in nitrogen-15. The invention also concerns certain diazirines of formula (I) likely to be obtained by the claimed synthesis method, and also refers to the .sup.15N.sub.2-diazirines of formula (I′). The claimed diazirines can be used in photoaffinity labelling. The .sup.15N.sub.2-diazirines can also be used in hyperpolarisation, in particular in the medical imaging field.

This disclosure features bis(diazirine) derivatives of the formulae (I) (1-a) or (1-b) that generate cross-linking in the cornea in response to exposure to an electromagnetic irradiation (e.g. UV-light). The compounds are useful, e.g. for treating a subject (e.g. a human) having a disease, disorder or condition in which abnormal shaping of the cornea (e.g. thinning of the cornea, e.g. bilateral thinning of the cornea, e.g. bilateral thinning of the central, paracentral, or peripheral cornea, or steepening (e.g., bulging) of the cornea) contributes to the pathology and/or symptoms, and/or progression of the disease, disorder or condition. Examples of such diseases, disorders or conditions include: (i) corneal ectatic disorders; (ii) vision conditions; and (iii) diseases, disorders, or conditions that are sequela or comorbid with any of the foregoing or any disclosed herein. More particular examples of such diseases, disorders or conditions include keratoconus, keratoglobus, pellucid marginal degeneration, corneal ectasia (e.g. postoperative ectasia, e.g. post-LASIK ectasia), Terrien's marginal degeneration, myopia, hyperopia, astigmatism, irregular astigmatism and presbyopia. In some embodiments, the claimed methods can be performed in the absence of added or supplemental oxygen levels, which can be advantageous in some applications. Preferred exemplary compounds are e.g. bis(diazirine) amino acid derivatives, such as e.g. example 1:

##STR00001##

This disclosure features bis(diazirine) derivatives of the formulae (I) (1-a) or (1-b) that generate cross-linking in the cornea in response to exposure to an electromagnetic irradiation (e.g. UV-light). The compounds are useful, e.g. for treating a subject (e.g. a human) having a disease, disorder or condition in which abnormal shaping of the cornea (e.g. thinning of the cornea, e.g. bilateral thinning of the cornea, e.g. bilateral thinning of the central, paracentral, or peripheral cornea, or steepening (e.g., bulging) of the cornea) contributes to the pathology and/or symptoms, and/or progression of the disease, disorder or condition. Examples of such diseases, disorders or conditions include: (i) corneal ectatic disorders; (ii) vision conditions; and (iii) diseases, disorders, or conditions that are sequela or comorbid with any of the foregoing or any disclosed herein. More particular examples of such diseases, disorders or conditions include keratoconus, keratoglobus, pellucid marginal degeneration, corneal ectasia (e.g. postoperative ectasia, e.g. post-LASIK ectasia), Terrien's marginal degeneration, myopia, hyperopia, astigmatism, irregular astigmatism and presbyopia. In some embodiments, the claimed methods can be performed in the absence of added or supplemental oxygen levels, which can be advantageous in some applications. Preferred exemplary compounds are e.g. bis(diazirine) amino acid derivatives, such as e.g. example 1:

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This disclosure relates to compounds, pharmaceutical compositions comprising them, and methods of using the compounds and compositions for treating diseases related to Heat Shock Transcription Factor 1 (HSF1) activity and/or function. More particularly, this disclosure relates to methods of inhibiting HSF1 activity with these compounds and pharmaceutical compositions thereof, and methods of treating diseases associated with HSF1 activity and/or function, such as cancer.

This disclosure relates to compounds, pharmaceutical compositions comprising them, and methods of using the compounds and compositions for treating diseases related to Heat Shock Transcription Factor 1 (HSF1) activity and/or function. More particularly, this disclosure relates to methods of inhibiting HSF1 activity with these compounds and pharmaceutical compositions thereof, and methods of treating diseases associated with HSF1 activity and/or function, such as cancer.

The present invention relates to compounds of formula (I): Formula (I) wherein Q is selected from O or S; L is a saturated or unsaturated, optionally substituted C.sub.1-C.sub.12 hydrocarbylene group optionally including one or more heteroatoms N, O or S; R.sup.1 is NR.sup.3R.sup.4, OR.sup.5, (CNR.sup.6)R.sup.7, (CO)R.sup.8, CN, N.sub.3, a quaternary ammonium group or an optionally substituted heterocycle; R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are each independently hydrogen or a saturated or unsaturated, optionally substituted C.sub.1-C.sub.10 hydrocarbyl group optionally including one or more heteroatoms N, O or S; wherein optionally L and R.sup.3, or L and R.sup.4, or R.sup.3 and R.sup.4, or L and R.sup.5, or L and R.sup.6, or L and R.sup.7, or R.sup.6 and R.sup.7, or L and R.sup.8 together with the atom(s) to which they are attached may form a 3- to 12-membered, saturated or unsaturated, optionally substituted cyclic group; and R.sup.2 is a cyclic group substituted at the a-position, wherein R.sup.2 may optionally be further substituted; provided that the atom of L which is attached to the sulfur atom of the sulfonylurea group is a carbon atom and is not a ring atom of a heterocyclic or aromatic group. The present invention further relates to salts, solvates and prodrugs of such compounds, to pharmaceutical compositions comprising such compounds, and to the use of such compounds in the treatment and prevention of medical disorders and diseases, most especially by the inhibition of NLRP.sub.3.

##STR00001##

A chemical compound is provided according to general formula (1):

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