Modified taxols, 4. Synthesis and biological activity of taxols modified in the side chain.
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.
D000470:Alkaloids / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis* / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D055598:Chemical Phenomena; D002621:Chemistry; D003500:Cyclization; D006801:Humans; D007624:KB Cells / Q000187:drug effects; D007941:Leukemia P388 / Q000188:drug therapy; D009682:Magnetic Resonance Spectroscopy; D017239:Paclitaxel; D015032:Zinc
D000470:Alkaloids; D000972:Antineoplastic Agents, Phytogenic; D015032:Zinc; D017239:Paclitaxel