Enzyme inhibitors synthesis

Short peptide chains in which one of the amino acid residues is replaced by a moiety related (or sometimes unrelated) to it appear with increased frequency in the literature. In the center of interest are enzyme inhibitors. Synthesis of these compounds is obviously determined by the reactivity of the unusual constituent and therefore it is hardly possible to set rules for such endeavours. We must confine the discussions therefore to generalities. For example chloromethylketones derived from certain amino acids are irreversible inhibitors which not merely interact but indeed react with the active site of an enzyme with the formation of a covalent bond. Chloromethyl ketones are synthesized by activation of the blocked amino acid followed by reaction with diazomethane to yield a diazoketone. This is transformed to the corresponding chloromethyl ketone by HCl in an organic solvent. From p-toluenesulfonyl-L-phenylalanine a chloromethyl ketone is obtained... 

Enzyme appHcations in organic synthesis Enzyme, inhibitors... 

Total synthesis of complex bioactive natural N-, 0-, and N,0-heterocycles, alkaloids, enzyme inhibitors, and herbicides 99YGK736. 

Total synthesis and development of some antibiotics and enzyme inhibitors 98YGK714. 

Suggest a synthesis for (76) needed for the synthesis of enzyme inhibitors. 

The methylation of deoxyuridine monophosphate (dUMP) to thymidine monophosphate (TMP), catalyzed by thymidylate synthase, is essential for the synthesis of DNA. The one-carbon fragment of methy-lene-tetrahydrofolate is reduced to a methyl group with release of dihydrofolate, which is then reduced back to tetrahydrofolate by dihydrofolate reductase. Thymidylate synthase and dihydrofolate reductase are especially active in tissues with a high rate of cell division. Methotrexate, an analog of 10-methyl-tetrahydrofolate, inhibits dihydrofolate reductase and has been exploited as an anticancer drug. The dihydrofolate reductases of some bacteria and parasites differ from the human enzyme inhibitors of these enzymes can be used as antibacterial drugs, eg, trimethoprim, and anti-malarial drugs, eg, pyrimethamine. 

A common procedure in C-C-bond formation is the aldol addition of enolates derived from carboxylic acid derivatives with aldehydes to provide the anion of the [5-hydroxy carboxylic acid derivative. If one starts with an activated acid derivative, the formation of a [Mac lone can follow. This procedure has been used by the group of Taylor [137] for the first synthesis of the l-oxo-2-oxa-5-azaspiro[3.4]octane framework. Schick and coworkers have utilized the method for their assembly of key intermediates for the preparation of enzyme inhibitors of the tetrahydrolipstatin and tetrahydroesterastin type [138]. Romo and coworkers used a Mukaiyama aldol/lac-tonization sequence as a concise and direct route to 3-lactones of type 2-253, starting from different aldehydes 2-251 and readily available thiopyridylsilylketenes 2-252 (Scheme 2.60) [139]. 

Although aminoacyl-tRNA synthetases are necessary for protein synthesis in all tissues, their importance in chemical carcinogenesis is difficult to assess. Mutation induction by this pathway has been studied extensively (123), yet metabolic activation in a carcinogen-target tissue has not been demonstrated. The only exception is hepatic prolyl-tRNA synthetase activation of N-hydroxy-Trp-P-2 however, hepatic O-acetylation of this substrate also occurs to an appreciable extent (12). Further investigations involving the use of specific enzyme inhibitors would be helpful in addressing this problem. 

There is considerable interest in imino-sugars and analogues as glycosidase enzyme inhibitors. The synthesis of a "homonojiritriazole" derivative 35 has now been reported... 

The initial hydroxylation of tryptophan, rather than the decarboxylation of 5-HTP, appears to be the rate-limiting step in serotonin synthesis. Therefore, the inhibition of this reaction results in a marked depletion of the content of 5-HT in brain. The enzyme inhibitor most widely used in experiments is parachlorophenylalanine (PCPA). In vivo, PCPA irreversibly inhibits tryptophan hydroxylase, presumably by incorporating itself into the enzyme to produce an inactive protein. This results in a long-lasting reduction of 5-HT levels. Recovery of enzyme activity, and 5-HT biosynthesis, requires the synthesis of new enzyme. Marked increases in mRNA for tryptophan hydroxylase are found in the raphe nuclei 1-3 days after administration of PCPA [6]. 

R. Wischnat, R. Martin, S. Takayama, C.-H. Wong, Che-moenzymatic Synthesis of Iminocyclitol Derivatives A Useful Library Strategy for the Development of Selective Fucosyltransfer Enzymes Inhibitors , Bioorg. Med, Chan. Lett. 1998, 8, 3353-3358. 

Some observed side-products (87 or 90) can be suppressed, for example by the use of modified catalysts (Pd(dba)2/4—6equiv. PPh3 instead of Pd(PPh3)4 in Eq. 14.10). Additional model studies demonstrated the utility of a-allenyl acetates and phosphates by the successful synthesis of pheromone (R)-94 [47] and of enzyme inhibitor 95 [48] (Scheme 14.20). 

The application of multiple reaction parameters executed in a parallel array format has been used to expedite the identification of optimal conditions for the synthesis of a collection of almost 600 new interleukin-1/ converting enzyme inhibitors [89]. The reaction in question was the problematic conversion of a / -tert-butyl aspartic acid bromoethylketone to the corresponding acyloxyketone (Scheme 2.63). The study en-... 

M., Cavrini, V. SAR of 9-amino-l,2,3,4-tetrahydroacridine-based acetylcholinesterase inhibitors synthesis, enzyme inhibitory activity, QSAR, and structure-based CoMEA of tacrine analogues./. Med. Chem. 2000, 43, 2007-2018. 

Thymine derivatives - 5-[7V-(2-Amino-4-hydroxy-6-methyl-5-pyrimidinyl-propyl)-p-carboxyanilinomethyl] uracil (XXXIII) was synthesized for study as a possible intermediate in the enzymatic synthesis of thymidylate. It is active as an enzyme inhibitor against thymidylate synthetase isolated from E. coli [298]. Certain thymine derivatives containing a 2-thioimidazole moiety (XXXIV, R = alkyl) inhibit growth of Ehrlich ascites carcinoma (fluid form) in mice [299]. 

The chemical synthesis of derivatives and emalogs has long coimnanded much interest, as such compounds are required for the study of structure—activity relationships in the action of trehalases (23,28), may serve as substitutes for 51 in the synthesis of cord-factor analogs to be used as probes in the field of mycobacterial biochemistry (29, 30), and could possibly prove to possess interesting properties as enzyme inhibitors or antibiotic agents. 

R. V. Stick, The synthesis of novel enzyme inhibitors and their use in defining the active sites of glycan hydrolases, Top. Curr. Chem., 187 (1997) 187—213. 

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