Lawrence M. Ballas

Synthesis and protein kinase C inhibitory activities of indane analogs of balanol

Abstract Regio- and stereoisomeric indane analogs (4–6) of balanol (−)-1, a potent protein kinase C (PKC) inhibitor, were synthesized in which the perhydroazepine of balanol was replaced by an indane nucleus. Analog (−)-4 and its racemic regioisomer 6 were found to have highly potent PKC inhibitory activities. In addition, compound (−)-4 displayed excellent kinase selectivity for PKC over PKA.

Synthesis and protein kinase C inhibitory activities of balanol analogues with modification of 4-hydroxybenzamido moiety

A series of racemic balanol analogues with modification of the benzamido moiety of balanol have been synthesized and evaluated for their inhibitory activities against human protein kinase C isozymes (PKC-alpha, -beta I, -beta II, -gamma, -delta, -epsilon, and -eta). The structural 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 group. in general, these analogues were found to be less potent than balanol, but a number of analogues were identified with improved isozyme selectivity. The structure-activity relationship studies of these analogues also indicated that (1) the optimal general PKC inhibition requires a free 4-hydroxyl group in the benzamido portion of the molecule, (2) the amide linkage of the benzamido moiety is important for PKC inhibition, 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 conformation of the benzamido moiety for optimal PKC inhibition suggests that the 4-hydroxyphenyl group may be involved in a specific inhibitor-enzyme interaction important for PKC inhibition.