Combretastatin A-4 (CA-4), the natural cis-stilbene, is a potent anticancer agent originally isolated from the bark of the South African Combretum caffrum tree. The compound strongly inhibits the polymerization of tubulin by binding to the colchicine site and induces selective vascular dysfunction in tumors by reducing the blood supply to them. This ability distinguishes CA-4 from other anticancer drugs, angiogenesis inhibitors for example, and defines it as a first member of new class of therapeutic compounds known as vascular disrupting agents.
We report here a new four-step approach for the preparation of natural combretastatin A-4. The method includes the Colvin rearrangement of the benzophenone derivative phenstatin to the key diarylalkyne followed by stereoselective semi-reduction to CA-4 in good overall yield. Currently, we are investigating the applicability of this method for the preparation of new heterocyclic analogues of combretastatin A-4.
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