Regioselective synthesis of water-soluble monophosphate derivatives of combretastatin A-1

The Natural Products combretastatin A-4 (CA4) and combretastatin A-1 (CA1) are potent Cancer vascular disrupting agents and inhibitors of tubulin assembly (IC₅₀ = 1-2 μM). The phosphorylated prodrugs CA4P and CA1P are undergoing human clinical trials against Cancer. CA1 is unique due to its incorporation of a vicinal phenol, which has afforded the opportunity to prepare both diphosphate and regioisomeric monophosphate derivatives. Here, we describe the first synthetic routes suitable for the regiospecific preparation of the CA1-monophosphates CA1MPA (8a/b) and CA1MPB (4a/b). The essential regiochemistry necessary to distinguish between the two vicinal phenolic groups was accomplished with a tosyl protecting group strategy. Each of the four monophosphate analogues (including Z and E isomers) demonstrated in vitro cytotoxicity against selected human Cancer cell lines comparable to their corresponding diphosphate congeners. Furthermore, Z-CA1MPA (8a) and Z-CA1MPB (4a) were inactive as inhibitors of tubulin assembly (IC₅₀ > 40 μM), as anticipated in this pure Protein Assay.