SYNTHESIS AND PROTEIN-KINASE-C INHIBITORY ACTIVITIES OF BALANOL ANALOGS WITH MODIFICATION OF 4-HYDROXYBENZAMIDO MOIETY

A series of racemic balanol analogues with modification of the benzami do moiety of balanol have been synthesized and evaluated for their inh ibitory activities against human protein kinase C isozymes (PKC-alpha, -beta I, -beta II, -gamma, -delta, -epsilon, and -eta). The structura l modification includes replacement of the 4-hydroxyphenyl group with variously substituted phenyl rings, substitution of the amide linkage with a sulfonamide or an ester, and replacement of the 4-hydroxyphenyl substructure with a hydroxyl substituted indole or a hydroxybenzyl gr oup. In general, these analogues were found to be less potent than bal anol, but a number of analogues were identified with improved isozyme selectivity. The structure-activity relationship studies of these anal ogues also indicated that (1) the optimal general PKC inhibition requi res a free 4-hydroxyl group in the benzamido portion of the molecule, (2) the amide linkage of the benzamido moiety is important for PKC inh ibition, and (3) the conformation associated with the benzamido moiety seems to have a profound effect on PKC inhibition. The requirement of a free 4-hydroxyl group in conjunction with an appropriate conformati on of the benzamido moiety for optimal PKC inhibition suggests that th e 4-hydroxyphenyl group may be involved in a specific inhibitor-enzyme interaction important for PKC inhibition. (C) 1997 Elsevier Science L td.