Our synthetic strategy to produce PK-C-interactive agents has started with diacylglycerol analogues embedded in more complicated ring structures to constrain orientation of pharmacophoric groups. This approach has yielded stable synthetic compounds with affinities (Ki) of 10 nM, already in the range of phorbol esters. The pattern of down regulation of protein kinase C isozymes induced by the most potent of our compounds differs from that of the typical tumor promoting phorbol ester, TPA. This altered down regulation which is the hallmark for the two known classes of regulatory domain-targeted protein kinase C inhibitors, the bryostatins and prostratin, indicates that the same effect can be achieved with simpler and more synthetically accessible molecules.
