Structural Simplification of Natural Products Toward the Generation of Biologically and Therapeutically Valuable Molecules: Analog Design of Naturally-Occurring Protein Kinase C Activators

Abstract

Indolactam-V (IL-V), bryostatin 1 (Bryo-1), and aplysiatoxin (ATX) are structurally diverse natural products that potently activate protein kinase C (PKC). Although they exhibit scientifically and therapeutically attractive bioactivities through PKC activation, their application for research and therapeutic uses has been limited by poor synthetic accessibility and complex biological profile. Recognizing this issue, we have designed structurally simpler and thus synthetically more accessible analogs of these PKC activators that can emulate or even improve biological performance of the parent natural products. IL-V analog was proved to be a useful tool for tracing PKC-mediated cellular signal transduction. Bryo-1 and ATX analogs have become promising leads for anti-cancer drugs. This study demonstrates that structural simplification of natural products provides biologically and therapeutically valuable molecules that are better suitable for human use.