Azaindolylsulfonamides, with a More Selective Inhibitory Effect on Histone Deacetylase 6 Activity, Exhibit Antitumor Activity in Colorectal Cancer HCT116 Cells

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• 作者：Hsueh-Yun Lee ; An-Chi Tsai ; Mei-Chuan Chen ; Po-Jung Shen ; Yun-Ching Cheng ; Ching-Chuan Kuo ; Shiow-Lin Pan ; Yi-Min Liu ; Jin-Fen Liu ; Teng-Kuang Yeh ; Jing-Chi Wang ; Chi-Yen Chang ; Jang-Yang Chang ; Jing-Ping Liou
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：May 22, 2014
• 年：2014
• 卷：57
• 期：10
• 页码：4009-4022
• 全文大小：577K
• 年卷期：v.57,no.10(May 22, 2014)
• ISSN：1520-4804

文摘

A series of indolylsulfonylcinnamic hydroxamates has been synthesized. Compound 12, (E)-3-(3-((1H-pyrrolo[2,3-b]pyridin-1-yl)sulfonyl)phenyl)-N-hydroxyacrylamide, which has a 7-azaindole core cap, was shown to have antiproliferative activity against KB, H460, PC3, HSC-3, HONE-1, A549, MCF-7, TSGH, MKN45, HT29, and HCT116 human cancer cell lines. Pharmacological studies indicated that 12 functions as a potent HDAC inhibitor with an IC₅₀ value of 0.1 渭M. It is highly selective for histone deacetylase 6 (HDAC6) and is 60-fold more active than against HDAC1 and 223-fold more active than against HDAC2. It has a good pharmacokinetic profile with oral bioavailability of 33%. In in vivo efficacy evaluations in colorectal HCT116 xenografts, compound 12 suppresses tumor growth more effectively than SAHA (1, N-hydroxy-N鈥?phenyloctanediamide) and is therefore seen as a suitable candidate for further investigation.