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 Journal Article

  

Authors:	Rivkin, A.; Yoshimura, F.; Gabarda, A. E.; Cho, Y. S.; Chou, T. C.; Dong, H.; Danishefsky, S. J.
Article Title:	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
Abstract:	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.
Keywords:	controlled study; unclassified drug; drug activity; drug efficacy; nonhuman; antineoplastic agents; paclitaxel; antineoplastic agent; mouse; animals; mice; animal model; colonic neoplasms; antineoplastic activity; drug screening; xenograft model antitumor assays; drug synthesis; breast neoplasms; tumors; breast carcinoma; lymphatic leukemia; colon carcinoma; patient treatment; mycobacterium; diseases; chemical reaction; synthesis (chemical); ring closing metathesis; antitumor agents; epothilones; epothilone derivative; metathesis; fludelone; humans; article; 9,10 dehydroepothilone
Journal Title:	Journal of the American Chemical Society
Volume:	126
Issue:	35
ISSN:	0002-7863
Publisher:	American Chemical Society
Date Published:	2004-09-08
Start Page:	10913
End Page:	10922
Language:	English
DOI:	10.1021/ja046992g
PROVIDER:	scopus
PUBMED:	15339176
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-4444339511&partnerID=40&md5=1eb583b08418ea71d97cd7bb3ebcf550
Notes:	J. Am. Chem. Soc. -- Cited By (since 1996):58 -- Export Date: 16 June 2014 -- CODEN: JACSA -- Source: Scopus

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