Total syntheses of [17]- and [18]dehydrodesoxyepothilones B via a concise ring-closing metathesis-based strategy: Correlation of ring size with biological activity in the epothilone series Journal Article

  

Authors:	Rivkin, A.; Njardarson, J. T.; Biswas, K.; Chou, T. C.; Danishefsky, S. J.
Article Title:	Total syntheses of [17]- and [18]dehydrodesoxyepothilones B via a concise ring-closing metathesis-based strategy: Correlation of ring size with biological activity in the epothilone series
Abstract:	A convergent ring-closing metathesis strategy has been employed for the highly concise syntheses of 10,11-dehydro-13,14-[17]desoxyepothilone B ([17]ddEpoB) and 10,11-dehydro-14,15-[18]desoxyepothilone B ([18]ddEpoB), which are 17- and 18-membered ring homologues of 10,11-dehydro-12,13-desoxyepothilone B ([16]ddEpoB or epothilone 490). We have demonstrated that the ring-closing metathesis (RCM) provides [17]ddEpoB or [18]ddEpoB with a high level of stereocontrol in the generation of the desired olefin in the products. These analogues were evaluated for antitumor activity. The results from the in vitro assays revealed that the [17]ddEpoB analogue is highly active against various tumor cell lines with a potency comparable to that of [16]ddEpoB. This is the first example of a 17-membered ring macrolactone epothilone that has retained its antitumor activity. In contrast, the biological data revealed that [18]ddEpoB is significantly less active than either [17]ddEpoB or the parent [16]ddEpoB.
Keywords:	unclassified drug; antineoplastic agents; antineoplastic activity; drug potency; in vitro study; drug screening assays, antitumor; cell line, tumor; drug synthesis; structure-activity relationship; correlation analysis; tumors; tumor cell line; neoplasm metastasis; esterification; molecular structure; inhibitory concentration 50; olefins; synthesis (chemical); stereochemistry; assays; epothilones; epothilone b; cells; aromatic compounds; ring-closing metathesis; humans; article; 10,11 dehydro 12,13 desoxyepothilone b; 10,11 dehydro 13,14 [17]desoxyepothilone b; 10,11 dehydro 14,15 [18]desoxyepothilone b
Journal Title:	Journal of Organic Chemistry
Volume:	67
Issue:	22
ISSN:	0022-3263
Publisher:	American Chemical Society
Date Published:	2002-11-01
Start Page:	7737
End Page:	7740
Language:	English
DOI:	10.1021/jo0204294
PUBMED:	12398497
PROVIDER:	scopus
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-0036827835&partnerID=40&md5=87a08e5c7d2cefc042820f9f796a4de0
Notes:	Export Date: 14 November 2014 -- Source: Scopus

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