Synthesis of peptidyl ene diones: selective inactivators of the cysteine proteinases.

A series of synthetic peptides in which the C-terminal carboxyl grouping (-CO(2)H) of each has been chemically converted into a variety of ene dione derivatives (-CO-CH=CH-CO-X; X = -H, -Me, -OBut, -OEt, -OMe, -CO-OMe), have been prepared and tested as inactivators against typical members of the serine and cysteine protease families. For example, the sequences Cbz-Pro-Phe-CH=CH-CO-OEt (I) which fulfils the known primary and secondary specificity requirements of the serine protease chymotrypsin, and Cbz-Phe-Ala-CH=CH-CO-OEt (II) which represents a general recognition sequence for cysteine proteases such as cathepsins B, L and S, have been tested as putative irreversible inactivators of their respective target proteases. It was found that, whereas II, for example, functioned as a time-dependent, irreversible inactivator of each of the cysteine proteases, I behaved only as a modest competitive reversible inhibitor of chymotrypsin. Within the simple ester sequences Cbz-Phe-Ala-CH=CH-CO-R, the rank order of inhibitor effectiveness decreases in the order R = -OMe > -OEt >> -OBut. It was also found that the presence of both an unsaturated double bond and an ester (or alpha-keto ester) moiety were indispensable for obtaining irreversible inactivators. Of the irreversible inactivators synthesized, Cbz-Phe-Ala-CH=CH-CO-CO-OEt (which contains a highly electrophilic alpha-keto ester grouping) was found to be the most effective exhibiting, for example, second-order rate constants of approximately 1.7 x 10(6)M(-1)min(-1) and approximately 4.9 x 10(4)M(-1)min(-1) against recombinant human cathepsin S and human spleenic cathepsin B, respectively. This initial study thus holds out the promise that this class of inactivator may well be specific for the cysteine protease subclass.

Diastereoselectivity in the Epoxidation of Substituted Cyclohexenes by Dimethyldioxirane(1)(,)(2).

Three series of compounds based on the cyclohexene framework have been epoxidized by dimethyldioxirane. A pronounced dependence of epoxide diastereoselectivity on substituent has been observed. In addition there is a solvent influence on this stereoselectivity. The results have been explained by invoking steric, H-bonding, and dipole-dipole influences on the epoxide stereochemistry.