247197-55-3

Upstream product

• 100-39-0 benzyl bromide 
• 215300-56-4 methyl (S)-(1-hydroxy-3-(4-hydroxy-2-nitrophenyl)propan-2-yl)carbamate 
• 1080-06-4 L-Tyr-OMe 
• 60-18-4 L-tyrosine 
• 215300-34-8 (S)-3-(4-hydroxyphenyl)-2-[(methoxycarbonyl)amino]-1-propanoic acid methyl ester 
• 215300-39-3 (S)-3-(4-hydroxy-3-nitrophenyl)-2-[(methoxycarbonyl)amino]-1-propanoic acid methyl ester 
• 215300-42-8 (S)-3-(4-acetoxy-3-acetamidophenyl)-2-[(methoxycarbonyl)amino]-1-propanoic acid methyl ester 
• 215300-45-1 (S)-O-acetyl-3-(4-acetoxy-3-acetamidophenyl)-2-[(methoxycarbonyl)amino]-1-propanol 

Downstream Products

• 215300-57-5 [(S)-2-(2-Amino-4-benzyloxy-phenyl)-1-hydroxymethyl-ethyl]-carbamic acid methyl ester 
• 215300-61-1 9-benzyloxy-5-hydroxymethyl-2-isopropyl-1,4,5,6-tetrahydro-2H-benzo[e][1,4]diazocin-3-one 
• 215300-63-3 (S,S)-9-benzoxybenzolactam-V₈ 
• 1027066-05-2 (S)-2-[2-((S)-2-Amino-3-hydroxy-propyl)-5-benzyloxy-phenylamino]-3-methyl-butyric acid 
• 215300-59-7 (2S)-N-[5-benzyloxy-2-[(S)-2-(methoxycarbonyl)amino-3-hydroxypropyl]phenyl]valine benzyl ester 

Relevant academic research and scientific papers

MULTI-FUNCTIONAL CHIMERIC MOLECULES

The present disclosure relates to multifunctional chemical conjugation molecules, which find utility as modifiers of target substrates. The present disclosure includes multifunctional compounds comprising a localizing moiety, a chemical linker moiety, an activator moiety, a first orienting adaptor interconnecting the chemical linker moiety on one end to the activator moiety, and optionally a second orienting adaptor interconnecting the chemical linker molecule on a different end to the localizing moiety. Molecules according to the present invention find use making post-translational modifications to macromolecules that are not the natural substrate of the activator moiety. Diseases or disorders may be treated or prevented with molecules of the present disclosure.

Phosphorylation-Inducing Chimeric Small Molecules

Small molecules have been classically developed to inhibit enzyme activity; however, new classes of small molecules that endow new functions to enzymes via proximity-mediated effect are emerging. Phosphorylation (native or neo) of any given protein-of-interest can alter its structure and function, and we hypothesized that such modifications can be accomplished by small molecules that bring a kinase in proximity to the protein-of-interest. Herein, we describe phosphorylation-inducing chimeric small molecules (PHICS), which enable two example kinases - AMPK and PKC - to phosphorylate target proteins that are not otherwise substrates for these kinases. PHICS are formed by linking small-molecule binders of the kinase and the target protein, and exhibit several features of a bifunctional molecule, including the hook-effect, turnover, isoform specificity, dose and temporal control of phosphorylation, and activity dependent on proximity (i.e., linker length). Using PHICS, we were able to induce native and neo-phosphorylations of BRD4 by AMPK or PKC. Furthermore, PHICS induced a signaling-relevant phosphorylation of the target protein Bruton's tyrosine kinase in cells. We envision that PHICS-mediated native or neo-phosphorylations will find utility in basic research and medicine.

General and stereospecific route to 9-substituted, 8,9-disubstituted, and 9,10-disubstituted analogues of benzolactam-V8

Nitration of the L-tyrosine derivative 9 provides the 3-nitro compound 13, which is converted into amide 15 by reduction and protection. Nitration of 15 either ortho or para to the acetamido group gives 16 and 17. After reduction of the nitro group, the anilines 21b and 29b are coupled with triflate 22a, and then cyclized to afford lactams 24 and 31, respectively. By means of a Pd-catalyzed coupling reaction, 8-acetamido-9-decynylbenzolactam- V8 (26) and 9-decynyl-10-acetamidobenzolactam-V8 (33) are obtained. The regioisomers 16 and 17 are transformed into a single isomer, 34, which is converted into 9-decynylbenzolactam-V8 (4). The K(i) values for 4, 26, and 33 to displace PDBU binding from recombinant PKCα (PKC = protein kinase C) are about 6, 173, and 46 nM. These results demonstrate that while the introduction of a substituent at either the 8- or 10-position of the 9- substituted benzolactam-V8s lowers their binding affinity, these newly generated analogues still retain reasonably good potency for PKC.

Stereospecific synthesis of 9-substituted benzolactam-V8 from L- tyrosine via regioselective aromatic nitration

A new protocol for the synthesis of 9-substituted benzolactam-V8, a class of potent protein kinase C activators, from L-tyrosine through regioselective aromatic nitration, is described.