The present disclosure provides the first asymmetric total synthesis and target identification of the curcusone natural products. The novel convergent synthesis is built upon a cheap and abundant chiral pool molecule (8) and features a thermal [3,3]-sigmatropic rearrangement and an FeCl3-promoted global hydrolysis/adol condensation cascade to rapidly construct the critical cycloheptadienone core. By performing chemoproteomics with the alkyne probe 37, we identified the previously “undruggable” oncogenic protein BRAT1 as a key cellular target of 1d. Furthermore, 1d inhibits BRAT1 in cancer cells, thereby reducing cancer cell migration, increasing susceptibility to DNA damage, and inducing chemosensitization to the approved drug etoposide. Compound 1d is the first known small-molecule inhibitor for BRAT1, a master regulator of the DDR and DNA repair. Composition matters and methods of uses are within the scope of this disclosure.

The present disclosure provides the first asymmetric total synthesis and target identification of the curcusone natural products. The novel convergent synthesis is built upon a cheap and abundant chiral pool molecule (8) and features a thermal [3,3]-sigmatropic rearrangement and an FeCl3-promoted global hydrolysis/adol condensation cascade to rapidly construct the critical cycloheptadienone core. By performing chemoproteomics with the alkyne probe 37, we identified the previously “undruggable” oncogenic protein BRAT1 as a key cellular target of 1d. Furthermore, 1d inhibits BRAT1 in cancer cells, thereby reducing cancer cell migration, increasing susceptibility to DNA damage, and inducing chemosensitization to the approved drug etoposide. Compound 1d is the first known small-molecule inhibitor for BRAT1, a master regulator of the DDR and DNA repair. Composition matters and methods of uses are within the scope of this disclosure.

The invention belongs to the pharmaceutical manufacturing field, which relates to a novel process for the preparation of substituted phenylacetic acids derivatives, especially relates to the preparation of 2-(4-(2-oxocyclopentyl)phenyl)propanoic acid. The process for the preparation of the precursor form of loxoprofen which use 1,4-di-halobenzyl compounds or disubstituted benzyl compounds as starting material, is through the substitution reaction of cyclopentanone groups or its precursor compounds.

##STR00001##

Wherein X is halogen, L.sub.1 is a suitable leaving group selected from halogen, OH, OMs, OTs, OTf and the like; L.sub.2 is a suitable leaving group selected from halogen, CN, OH, CH.sub.2OH, CHO, CH.sub.3NO.sub.2, ester group, NR.sub.4R.sub.5, OTf, OTs, OMs, CCR.sub.6, CCR.sub.7 and the like, wherein R.sub.4, R.sub.5, R.sub.6, R.sub.7 are short chain alkyl groups; Z is cyclopentanone group and its precursor form selected from

##STR00002##

and the like; R.sub.3 is short chain alkyl groups. L.sub.3 is a suitable leaving group selected from halogen, OH, OMs, OTs, OT.sub.f and the like, or organometallic groups. The invention also include the detailed procedure to convert the precursor compounds of cyclopentanone group to cyclopentanone, followed by the transformation of the precursor compounds of loxoprofen to loxoprofen.

The invention belongs to the pharmaceutical manufacturing field, which relates to a novel process for the preparation of substituted phenylacetic acids derivatives, especially relates to the preparation of 2-(4-(2-oxocyclopentyl)phenyl)propanoic acid. The process for the preparation of the precursor form of loxoprofen which use 1,4-di-halobenzyl compounds or disubstituted benzyl compounds as starting material, is through the substitution reaction of cyclopentanone groups or its precursor compounds.

##STR00001##

Wherein X is halogen, L.sub.1 is a suitable leaving group selected from halogen, OH, OMs, OTs, OTf and the like; L.sub.2 is a suitable leaving group selected from halogen, CN, OH, CH.sub.2OH, CHO, CH.sub.3NO.sub.2, ester group, NR.sub.4R.sub.5, OTf, OTs, OMs, CCR.sub.6, CCR.sub.7 and the like, wherein R.sub.4, R.sub.5, R.sub.6, R.sub.7 are short chain alkyl groups; Z is cyclopentanone group and its precursor form selected from

##STR00002##

and the like; R.sub.3 is short chain alkyl groups. L.sub.3 is a suitable leaving group selected from halogen, OH, OMs, OTs, OT.sub.f and the like, or organometallic groups. The invention also include the detailed procedure to convert the precursor compounds of cyclopentanone group to cyclopentanone, followed by the transformation of the precursor compounds of loxoprofen to loxoprofen.

Provided are colored 1,4-benzoquinone compounds obtained by oxidation of precursor molecules from the venom of the scorpion Diplocentrus melici (Diplocentridae family). Schemes for the chemical synthesis of these compounds using reagents commercially available are also provided. Biological assays show that the red compound (3,5-dimethoxy-2-(methylthio)cyclohexa-2,5-diene-1,4-dione) is very effective at killing Staphylococcus aureus and that the blue compound (5-methoxy-2,3-bis(methylthio)cyclohexa-2,5-diene-1,4-dione) has remarkable activity against Mycobacterium tuberculosis. The blue compound is effective against multi-drug-resistant tuberculosis (MDR-TB) and is not detrimental to lung epithelium. Both compounds were found to be cytotoxic to human neoplastic cell lines and to mononuclear cells (PBMCs).

Provided are colored 1,4-benzoquinone compounds obtained by oxidation of precursor molecules from the venom of the scorpion Diplocentrus melici (Diplocentridae family). Schemes for the chemical synthesis of these compounds using reagents commercially available are also provided. Biological assays show that the red compound (3,5-dimethoxy-2-(methylthio)cyclohexa-2,5-diene-1,4-dione) is very effective at killing Staphylococcus aureus and that the blue compound (5-methoxy-2,3-bis(methylthio)cyclohexa-2,5-diene-1,4-dione) has remarkable activity against Mycobacterium tuberculosis. The blue compound is effective against multi-drug-resistant tuberculosis (MDR-TB) and is not detrimental to lung epithelium. Both compounds were found to be cytotoxic to human neoplastic cell lines and to mononuclear cells (PBMCs).

Methods for preparing a variety of ladderane precursors, ladderane compounds and ladderane lipids are provided. Also provided are methods of preparing a liposome from the ladderane lipids disclosed herein, and compositions thereof. Aspects of the invention include encapsulated one or more cargo moieties in the liposome or compositions thereof and use of the subject liposome compositions as vehicles in drug delivery, imaging, diagnostics and other medical applications. Aspects of the methods disclosed herein include administering a liposomal composition comprising a pharmaceutical agent to a subject under conditions sufficient to deliver the composition to a site of interest in the subject, and release the pharmaceutical agent from the liposomal composition.

Methods for preparing a variety of ladderane precursors, ladderane compounds and ladderane lipids are provided. Also provided are methods of preparing a liposome from the ladderane lipids disclosed herein, and compositions thereof. Aspects of the invention include encapsulated one or more cargo moieties in the liposome or compositions thereof and use of the subject liposome compositions as vehicles in drug delivery, imaging, diagnostics and other medical applications. Aspects of the methods disclosed herein include administering a liposomal composition comprising a pharmaceutical agent to a subject under conditions sufficient to deliver the composition to a site of interest in the subject, and release the pharmaceutical agent from the liposomal composition.

Methods for preparing a variety of ladderane precursors, ladderane compounds and ladderane lipids are provided. Also provided are methods of preparing a liposome from the ladderane lipids disclosed herein, and compositions thereof. Aspects of the invention include encapsulated one or more cargo moieties in the liposome or compositions thereof and use of the subject liposome compositions as vehicles in drug delivery, imaging, diagnostics and other medical applications. Aspects of the methods disclosed herein include administering a liposomal composition comprising a pharmaceutical agent to a subject under conditions sufficient to deliver the composition to a site of interest in the subject, and release the pharmaceutical agent from the liposomal composition.

Some embodiments of the invention include inventive catalysts (e.g., compounds of Formula (I) or (Ia)). Other embodiments include compositions comprising the inventive catalysts. Some embodiments include methods of using the inventive catalysts (e.g., in hydrofluorination of an organic compound). Further embodiments include methods for making the inventive catalysts. Additional embodiments of the invention are also discussed herein.