Azaindolylsulfonamides, with a more selective inhibitory effect on histone deacetylase 6 activity, exhibit antitumor activity in colorectal cancer HCT116 cells

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

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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 μM. 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′- phenyloctanediamide) and is therefore seen as a suitable candidate for further investigation.

Original languageEnglish
Pages (from-to)4009-4022
Number of pages14
JournalJournal of Medicinal Chemistry
Issue number10
Publication statusPublished - May 22 2014


ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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