Accession Number : ADA332669

Title :   Anticancer Agents Based on a New Class of Transition-State Analog Inhibitors for Serine and Cysteine Proteases.

Descriptive Note : Annual rept. 1 Aug 96-31 Jul 97

Corporate Author : BROWN UNIV PROVIDENCE RI

Personal Author(s) : Seto, Christopher T.

PDF Url : ADA332669

Report Date : AUG 1997

Pagination or Media Count : 58

Abstract : A new class of competitive inhibitors for serine and cysteine proteases is described. These compounds are potential anticancer agents that would act by inhibiting metastasis and angiogenesis. The first part of this report describes inhibitors that are based upon a 4-heterocyclohexanone ring, and are designed to react with the enzyme active site nucleophile to give a reversibly formed hemithioketal. The electrophilicity of the ketone in these inhibitors is enhanced by ring strain and by through-space electrostatic repulsion with the heteroatom at the 1-position of the ring. In the second part, 13C Nuclear Magnetic Resonance spectroscopy is used to investigate the mechanism of inhibition of the cysteine protease papain by 4-heterocyclohexanones. A tetrahydropyranone-based inhibitor has been synthesized that incorporates a 13C label at the electrophilic ketone moiety. Reaction of this inhibitor with a stoichiometric amount of papain can be monitored by 13C NMR spectroscopy, which shows a new resonance at 86.4 ppm. This new resonance is identified as a covalent hemithioketal adduct between the ketone of the inhibitor and the active site cysteine nucleophile. The tetrahedral geometry of this reversibly formed hemithioketal adduct mimics the intermediate that occurs during enzyme catalyzed hydrolysis of peptides.

Descriptors :   *CYSTEINE, *PEPTIDE HYDROLASES, *SERINE, *CHEMOTHERAPEUTIC AGENTS, SPECTROSCOPY, ENZYMES, RESONANCE, GEOMETRY, INHIBITION, HYDROLYSIS, BLOOD VESSELS, KETONES, METASTASIS, PAPAIN.

Subject Categories : Biochemistry
      Medicine and Medical Research

Distribution Statement : APPROVED FOR PUBLIC RELEASE