Developments of isoCombretastatin A-4 derivatives as highly cytotoxic agents

Combretastatin A-4 (CA-4) is a natural anti-cancer agent isolated in 1989 from the African willow tree, Combretum caffrum. Due to its chemical simplicity, this (Z)-stilbene has been the subject of many structural modifications mainly to improve its chemical and metabolic stability. Beside a large number of synthetic analogues, isoCombretastatin A-4 (isoCA-4), has proved to be a solution of choice since this non-natural isomer of CA-4 is stable, easier to synthesize and has equivalent antitumor properties as CA-4. In this review, we will present the structure-activity relationships (SARs) around isoCA-4 since its discovery in 2007. In a first part, we will describe some alternatives to replace the phenol B-ring of isoCA-4, then we will focus on the variations made on the 1,1-ethylene double bond and then, we will evocate very recent exiting results concerning the possible replacements of the 3,4,5-trimethoxyphenyl A-ring of isoCA-4 by suitable heterocycles.