A common pharmacophore for cytotoxic natural products that stabilize microtubules

Taxol (paclitaxel), a complex diterpene obtained from the Pacific yew, Taxu s brevifolia, is arguably the most important new drug in cancer chemotherap y, The mechanism of cytotoxic action for paclitaxel-i.e., the stabilization of microtubules leading to mitotic arrest-is now shared by four recently i dentified natural products, eleutherobin, epothilones A and B, and discoder molide. Their ability to competitively inhibit [H-3]paclitaxel binding to m icrotubules strongly suggests the existence of a common binding site. Recen tly, we have developed nonaromatic analogues of paditaxel that maintain hig h cytotoxicity and tubulin binding (e.g., nonataxel). We now propose a comm on pharmacophore that unites paclitaxel, nonataxel, the epothilones, eleuth erobin, and discodermolide, and rationalizes the extensive structure-activi ty relationship data pertinent to these compounds, Insights from the common pharmacophore have enabled the development of a hybrid construct with demo nstrated cytotoxic and tubutin-binding activity.