期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 18, 期 23, 页码 6268-6272出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2008.09.109
关键词
Total synthesis; Macrolide; Anticancer; Tubulin
资金
- NIH [CA-93455]
- EPSRC
- AstraZeneca
By exploiting a Still-Gennari olefination of a common C11-C26 aldehyde with a C4-C10 or C1-C10 beta-ketophosphonate, three modified C2-C6 region analogues of the 22-membered macrolide dictyostatin were synthesised and evaluated in vitro for growth inhibition against a range of human cancer cell lines, including the Taxol-resistant NCI/ADR-Res cell line. 6-Desmethyldictyostatin and 2,3-dihydrodictyostatin displayed potent (low nanomolar) antiproliferative activity, intermediate between dictyostatin and discodermolide, while 2,3,4,5-tetrahydrodictyostatin showed activity comparable to discodermolide. As with dictyostatin, these simplified analogues act through a mechanism of microtubule stabilisation, G2/M arrest and apoptosis. (C) 2008 Elsevier Ltd. All rights reserved.
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