666739-81-7Relevant articles and documents
Discovery of (E)-9,10-dehydroepothilones through chemical synthesis: On the emergence of 26-trifluoro-(E)-9,10-dehydro-12,13-desoxyepothilone B as a promising anticancer drug candidate
Rivkin, Alexey,Yoshimura, Fumihiko,Gabarda, Ana E.,Cho, Young Shin,Chou, Ting-Chao,Dong, Huajin,Danishefsky, Samuel J.
, p. 10913 - 10922 (2004)
We provide a full account of the discovery of the (E)-9,10-dehydro derivatives of 12,13-desoxyepothilone B (dEpoB), a new class of antitumor agents with promising in vivo preclinical properties. The compounds, which are to date not available by modification of any of the naturally occurring epothilones, were discovered through total chemical synthesis. We describe how our investigations of ring-closing metathesis reactions in epothilone settings led to the first and second generation syntheses of (E)-9,10-dehydro-12,13- desoxyepothilone congeners. With further modifications, the synthesis was applied to reach a 26-trifluoro derivative compound (see compound 7). To conduct such studies and in anticipation of future development needs, the total synthesis which led to the initial discovery of compound 7 was simplified significantly. The total synthesis methodology used to reach compound 7 was then applied to reach more readily formulated compounds, bearing hydroxy and amino functionality on the 21-position (see compounds 45,62, and 63). Following extensive in vitro evaluations of these new congeners, compound 7 was nominated for in vivo evaluations in xenograft models. The data provided herein demonstrate a promising therapeutic efficacy, activity against large tumors, nonrelapseability, and oral activity. These results have identified compound 7 as a particularly promising compound for clinical development. The excellent, totally synthetic, route to 7 makes such a program quite feasible.
SYNTHESIS OF EPOTHILONES, INTERMEDIATES THERETO, ANALOGUES AND USES THEREOF
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Page 87, (2008/06/13)
The present invention provides compounds of formula (I): as described generally and in classes and subclasses herein. The present invention additionally provides pharmaceutical compositions comprising compounds of formula (I) and provides methods of treating cancer comprising administering a compound of formula (I).
