Synthesis and Antiproliferative Activities of Ottelione A Analogues

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• 作者：Tsai-Yuan Chang ; Yun-Peng Tu ; Win-Yin Wei ; Hsiang Yu Chen ; Chih-Shang Chen ; Ying-Shuan E. Lee ; Jiann-Jyh Huang ; Chin-Kang Sha
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2012
• 出版时间：December 13, 2012
• 年：2012
• 卷：3
• 期：12
• 页码：1075-1080
• 全文大小：318K
• 年卷期：v.3,no.12(December 13, 2012)
• ISSN：1948-5875

文摘

Through the syntheses of its C-1 desvinyl, C-7 methylene, C-7 exocyclic ethylidene, and various C-3 phenylmethyl analogues, the structure鈥揳ctivity relationship of antimitotic ottelione A (4) against tubulin and various cancer cells was established. The results indicated that compound 4 was a colchicine-competitive inhibitor and that the C-1 vinyl group is unnecessary for its potency, whereas the C-7 exocyclic double bond is essential, possibly because of its irreversible interaction with tubulin. Further optimization of the substituents on the phenylmethyl group at the C-3 position generated compound 10g with a 3鈥?fluoro-4鈥?methoxyphenylmethyl substituent, which was 6鈥?8-fold more active against MCF-7, NCI-H460, and COLO205 cancer cells relative to 4. Results from in vitro tubulin polymerization assay confirmed the potency of compounds 4, 10g, and 11a.

Keywords:

ottelione A; antimitotic; tubule&qsSearchArea=searchText">microtubule; tubulin&qsSearchArea=searchText">tubulin; anticancer