Peptide chloromethylketones

The cysteinyl proteases include papain calpains I and II cathepsins , H, and L proline endopeptidase and interleukin-converting enzyme (ICE) and its homologs. The most well-studied cysteinyl protease is likely papain, and the first x-ray crystallographic structures of papain [193] and a peptide chloromethylketone inhibitor-papain complex [194] provided the first high resolution molecular maps of the active site. Pioneering studies in the discovery of papain substrate peptide-based inhibitors having P, electrophilic moieties such as aldehydes [195], ketones (e.g., fluoromethylketone, which has been determined [196] to exhibit selectivity for cysteinyl proteases versus serinyl proteases), semicarbazones, and nitriles are noteworthy since 13C-NMR spectro-... 

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... 

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