Studies On The Synthesis Of Some Water-soluble Produrgs Of Cytotoxic Agent Combretastatin A-4

Combretastatin A-4 (11) is a natural product isolated from the bark of a South African tree Combretum caffrum. This substance can strongly inhibit the polymerization of tubulim by binding to the colchicine-binding site. CA4 exhibits excellent cytotoxity against various human cancer cells including multidrug resistant (MDR) cancer cell lines. However, CA4 itself was prevented from entering clinical trial due to the poor solubility in pharmaceutically acceptable solvents. In order to create a prodrug with such property, several groups have reported the synthesis of the prodrugs of CA4 with increased aqueous solubility. The most important one is disodium phosphate prodrug of CA4 (CA4P), which is currently undergoing the phase II/III clinical trials. As a tumor vascular targeting agent, CA4P displays potent antivuscular/anticacer activity while causing no significant blood flow retention in normal tissues.On the other hand, phosphoryl choline (PC) is an essential part of cell membrane bounding phospholipids, and contributes to the hydrophicity of such amphiphiles. Over the past years PC have been widely applied to produce biomimetic, hemocompatible and biodegradable polymers. However, to the best of our knowledge, there is no specific report about PC as water-soluble moiety for the synthesis of prodrugs. We speculate that a prodrug containing a PC structure would not only have better aqueous solubility, but also be biodegradable and biocompatible with living environment.Since the amount of CA4 in the bark of Combretum caffrum is very low, the isolation of this compound is quite difficult. Therefore, the development of efficient methods for the total synthesis of CA4 has triggered intensive interests over the past...