SYNTHESIS AND PROTEIN-KINASE-C INHIBITORY ACTIVITIES OF ACYCLIC BALANOL ANALOGS THAT ARE HIGHLY SELECTIVE FOR PROTEIN-KINASE-C OVER PROTEIN-KINASE-A

A series of balanol analogs in which the perhydroazepine ring and the p-hydroxybenzamide moiety were combined into an acyclic linked unit ha ve been prepared and evaluated for their inhibitory properties against the serine/threonine kinase PKC. Several low-micromolar to low-nanomo lar inhibitors of the alpha, beta(I), beta(II), gamma, delta, epsilon, and eta PKC: isozymes were prepared. In general, these acyclic balano l analogs were found to be highly selective for PKC over the serine/th reonine kinase PKA. The type and number of atoms linking the benzophen one ester to the p-hydroxyphenyl group necessary for optimal PKC inhib ition were investigated. The most potent compounds contained a three-c arbon linker in which the carboxamide moiety of balanol had been repla ced by a methylene group. The effect of placing substituents on the th ree-carbon chain was also investigated. The preferred compounds contai ned either a 2-benzenesulfonamido (6b) or a 1-methyl (21b) substituent . The preferred compounds 6b and 21b were tested against a panel of se rine/threonine kinases and found to be highly selective for PKC. The m ore active enantiomer of 6b, (S)-12b, was 3-10-fold more active than t he R-enantiomer against the PKC isozymes. The effect of making the ana logs more rigid by making the three-carbon chain part of a five-member ed ring, but with retention of the methylene replacement for the carbo xamide moiety, led to potent PKC inhibitors including anti-substituted pyrrolidine analog 35b and the most potent PKC inhibitor in the serie s, anti-substituted cyclopentane analog 29b. The anti cyclopentane ana log 29b was a low-micromolar inhibitor of the PMA-induced superoxide b urst in neutrophils, and its carboxylic ester was a high-nanomolar inh ibitor of neutrophils. Finally esterification of 21b, (S)-12b, and 35b turned these potent PKC inhibitors into low-micromolar inhibitors of neutrophils.