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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Abstract

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
Volume57
Issue number10
DOIs
Publication statusPublished - May 22 2014

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HCT116 Cells
Histone Deacetylases
Colorectal Neoplasms
Histone Deacetylase Inhibitors
Heterografts
Biological Availability
Inhibitory Concentration 50
Neoplasms
Pharmacokinetics
Pharmacology
Cell Line
Growth
vorinostat
7-azaindole dimer

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Azaindolylsulfonamides, with a more selective inhibitory effect on histone deacetylase 6 activity, exhibit antitumor activity in colorectal cancer HCT116 cells. / Lee, Hsueh Yun; Tsai, An Chi; Chen, Mei Chuan; Shen, Po Jung; Cheng, Yun Ching; Kuo, Ching Chuan; Pan, Shiow Lin; Liu, Yi Min; Liu, Jin Fen; Yeh, Teng Kuang; Wang, Jing Chi; Chang, Chi Yen; Chang, Jang Yang; Liou, Jing Ping.

In: Journal of Medicinal Chemistry, Vol. 57, No. 10, 22.05.2014, p. 4009-4022.

Research output: Contribution to journalArticle

Lee, Hsueh Yun ; Tsai, An Chi ; Chen, Mei Chuan ; Shen, Po Jung ; Cheng, Yun Ching ; Kuo, Ching Chuan ; Pan, Shiow Lin ; Liu, Yi Min ; Liu, Jin Fen ; Yeh, Teng Kuang ; Wang, Jing Chi ; Chang, Chi Yen ; Chang, Jang Yang ; Liou, Jing Ping. / Azaindolylsulfonamides, with a more selective inhibitory effect on histone deacetylase 6 activity, exhibit antitumor activity in colorectal cancer HCT116 cells. In: Journal of Medicinal Chemistry. 2014 ; Vol. 57, No. 10. pp. 4009-4022.
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T1 - Azaindolylsulfonamides, with a more selective inhibitory effect on histone deacetylase 6 activity, exhibit antitumor activity in colorectal cancer HCT116 cells

AU - Lee, Hsueh Yun

AU - Tsai, An Chi

AU - Chen, Mei Chuan

AU - Shen, Po Jung

AU - Cheng, Yun Ching

AU - Kuo, Ching Chuan

AU - Pan, Shiow Lin

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AU - Liu, Jin Fen

AU - Yeh, Teng Kuang

AU - Wang, Jing Chi

AU - Chang, Chi Yen

AU - Chang, Jang Yang

AU - Liou, Jing Ping

PY - 2014/5/22

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