| The phorboxazoles are singular natural products that combine complex heterocyclic structures with unprecedented cytostatic and apoptotic activities against human cancer cells. The overall goals of our phorboxazole project are to employ a combination of synthetic and biological methods to capture the potential of phorboxazoles and their cellular targets as new leads for therapeutic development. The prerequisite for rewarding research toward this goal is efficient and flexible synthesis of phorboxazoles and, more informatively and practically, their structural analogs. Our original tri-component coupling strategy designed for the first total synthesis of phorboxazole A has been extended to the generation of analogs for probing the biological mode of action.; Described herein is an innovative approach to the C1--C30 (2 Z)-macrolide containing domain of phorboxazole A, deploying a regio- and stereoselective ring-closing metathesis (RCM) strategy. This work demonstrates a dramatic effect of reaction solvent on (E/Z)-distribution of RCM products. Based on our de novo biomimetic oxazole formation strategy, a total synthesis of potent S phase cytostatic 33- O-Methyl-45,46-dehydrobromophorboxazole A is achieved via tri-component sequential amide coupling and simultaneous oxazole generation. This 19 linear steps approach represents the most efficient synthetic access to the phorboxazole architecture and enables a combinatorial generation of a phorboxazole analog library.; Fluorescence anisotropy, surface plasmon resonance and equilibrium dialysis are explored to quantify the interaction of phorboxazole derivates with their relevant cellular binding partners, in order to develop an in vitro assay for rapid identification of lead compound for cancer therapy with the aid of diversity-oriented synthesis. |
