Semisynthesis of 7-Deoxypaclitaxel Derivatives Devoid of an Oxetane D-Ring, Starting from Taxine B

Six 7‐deoxypaclitaxel derivatives have been prepared from taxine B; they contribute to understanding of the effect of the oxetane D‐ring in paclitaxel on the cytotoxic activity of paclitaxel. Three of these analogues each contain a double bond instead of a D‐ring at the C‐4 position, while two others each contain a three‐membered ring in place of the oxetane ring. Both the C‐4 double bond and the small D‐ring in these paclitaxel derivatives were intended to act as substitutes for the paclitaxel oxetane D‐ring and were expected to impose on the taxane skeleton and the pendant groups a kind of rigidity and conformation similar to that produced by the oxetane ring in paclitaxel. All the derivatives demonstrated considerably reduced in vitro cytotoxic activity − relative to paclitaxel − against a panel of seven well‐characterized human tumor cell lines. The general picture coming out of the structure‐activity relationships of the paclitaxel derivatives reported here is that the presence of an oxygen atom at a spatial position resembling that of the oxygen atom in the oxetane ring of paclitaxel is important if a paclitaxel derivative is to retain considerable cytotoxic activity. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)