Combretastatins A-4 and A-1 and their derivatives: Review

This modern literature review covers the results of study of the tubulin inhibitors, mainly combretastatins A-4 and A-1 (CA-4 and CA-1) or colhicinoids. The article presents data of SAR (Structure Activity Relation) study of numerous CA-4 analogues as well as mechanisms of their action evaluated in vitro (using cultured tumor cells) and in vivo (using animals with transplanted murine tumors or with xenografts of human tumors of various histogenesis). The phosphate CA-4 derivative (CA-4P) is characterized as a vascular disrupting agent (VDAs). Approaches are described for developing CA-4 analogues stable in cis-configuration as well as methods for enhancing hydrophility of promising derivatives along with retention of their high cytotoxicity. The results of various clinical trials both of CA-4P and CA-1P administered individually or in combination with chemotherapeutic drugs are also presented. Our conclusion is that despite numerous studies performed during the last thirty years no ideal water-soluble molecule with stable cis-configuration and high cytotoxic activity has been obtained which could become the basis of an active anti-tumor medicine. The aim of the review is to present the systematic data on antitumor activity of combretastatin CA-4 and CA-1 analogues as well as the modes of their modification and therapeutic usage.