Modified taxols, 4. Synthesis and biological activity of taxols modified in the side chain.

Abstract

A number of taxol derivatives substituted at the 2' position of the side chain have been prepared and their biological activities determined in KB cell culture and/or the P-388 in vivo assay. The 2'-(t-butyldimethylsilyl)taxol 5 is essentially inactive, indicating the need for a free hydroxyl group at the 2' position for activity. Epimerization of the 2' position occurred on treatment of 2'-acetyltaxol derivatives with 1,5-diazabicyclo[5.4.0]undec-7-ene, but treatment of 2'-(2,2,2-trichloroethyloxycarbonyl) taxol derivatives with DBU yielded the novel cyclization products 11 and 12 and, after deprotection at the 7 position, 13. The derivative 13 is also essentially inactive in the KB test system. Two taxols with increased H2O solubility were prepared, the 2'-(beta-alanyl) derivative 15 and the 2'-succinyl derivative 16. Although both these derivatives were active in vivo and in vitro, the former was too unstable and the latter not active enough to make suitable H2O-soluble derivatives of taxol.