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The University of Southampton

Research project: Harrowven: Synthesis of Combretastatin A-4 and Related Analogues

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Though structurally simple, combretastatin A-4, from the African Bush Willow Combretum caffrum (Combretaceae), is a potent inhibitor of cancer cell growth and a competitive inhibitor of colchicine binding to tubulin.

It is a potent inhibitor of mitosis and microtubule assembly and is capable of inducing irreversible vascular shutdown within solid tumours while leaving normal vasculature intact. Poor bioavailability for combretastatin A-4 led to the development of sodium phosphate analogue, which advanced to Phase I human cancer clinical trials in 1998 and is currently undergoing evaluation in human cancer Phase II and combination trials. We recently describe a new approach to combretastatin A-4 that exploits co-operative ortho-effects in Wittig reactions to achieve high (Z)-selectivity in the olefination reaction.

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Dose response assays demonstrated that combretastatin A-4 and its o,o'-dibromideinhibited ZR-75-1 cell growth with EC50 values of 3.5±2.3 and 51±4.0 nM, respectively. Growth inhibition was shown to be due to inhibition of microtubule polymerization, with both compounds inducing cell cycle arrest in the G2M phase of the cell cycle and increased Bcl-2 phosphorylation, consistent with acting as anti-tubulin agents.

Related research groups

Organic Chemistry: Synthesis, Catalysis and Flow
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