Tumor vasculature represents an important therapeutic target in the treatment of cancer. Tumor vessels are significantly different in structure from normal vasculature and are subject to rapid proliferation of endothelial cells and formation of highly disorganized microvessels. Combretastatin A-1 (CA1) and combretastatin A-4 (CA4) are among a class of vascular disrupting agents (VDAs) isolated from the bushwillow tree Combretum caffrum by George R. Pettit (Arizona State University). Water-soluble phosphate prodrug salts of these compounds have been prepared. VDAs selectively damage existing tumor vasculature leading to blood flow reduction and tumor necrosis. Many combretastatin analogues have been prepared synthetically, and nitrogen-bearing derivatives are especially noteworthy. The 3-amino-combretastatin serinamide prodrug (AVE8062, compound 4) is one example. In an effort to discover new VDAs with good water solubility, amino acid prodrugs of diamino-CA1 (3) and its fluorine substituted congeners were synthesized. These compounds were evaluated in terms of their ability to inhibit tubulin polymerization and for their cytotoxicity (in vitro) against selected human cancer lines. The hydrochloride salt (KGP322) of compound 3 demonstrated significant disruption of a capillary-like network of tubules (from HUVECs) at a concentration of 0.1 �M and caused a > 90% reduction in blood flow (at 2 h) as evidenced by bioluminescence imaging (BLI) in a SCID mouse model at a dose of 80 mg/kg, thus demonstrating the vascular damaging capability of this compound.

Synthesis and biological evaluation of combretastatin water-soluble amino acid prodrugs

246th National Meeting (2013)

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