Synthesis and Structure-Activity Relationships of Novel 2', 2'-Difluoro Analogues of Docetaxel

抄録

To investigate the role of the 2'-hydroxy group at the C-13 side chain of docetaxel in the antitumor activity, we prepared several 2', 2'-difluoro derivatives of docetaxel and evaluated their cytotoxicity against mouse leukemia and human tumor cell lines and their microtubule disassembly-inhibitory activity. These analogues were prepared by esterification of protected 10-deacetylbaccatin III (21) with appropriate α, α-difluorinated carboxylic acids (Charts 1 and 2). Among these 2', 2'-difluorodocetaxel derivatives, 2', 2'-difluorodocetaxel (23b) was approximately 3-10 times as active as 2'-fluorodocetaxel (29a) in terms of cytotoxicity. In addition, the 3'-(2-furyl) (23h) and 3'-(2-pyrrolyl)(23p) analogues showed activity comparable or superior to that of docetaxel (2).