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

doi:10.1021/jm401899x

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

Research output: Contribution to journal › Article › peer-review

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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 language	English
Pages (from-to)	4009-4022
Number of pages	14
Journal	Journal of Medicinal Chemistry
Volume	57
Issue number	10
DOIs	https://doi.org/10.1021/jm401899x
Publication status	Published - May 22 2014

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1021/jm401899x

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Lee, H. Y., Tsai, A. C., Chen, M. C., Shen, P. J., Cheng, Y. C., Kuo, C. C., Pan, S. L., Liu, Y. M., Liu, J. F., Yeh, T. K., Wang, J. C., Chang, C. Y., Chang, J. Y., & Liou, J. P. (2014). Azaindolylsulfonamides, with a more selective inhibitory effect on histone deacetylase 6 activity, exhibit antitumor activity in colorectal cancer HCT116 cells. Journal of Medicinal Chemistry, 57(10), 4009-4022. https://doi.org/10.1021/jm401899x

Lee, HY, Tsai, AC, Chen, MC, Shen, PJ, Cheng, YC, Kuo, CC, Pan, SL , Liu, YM, Liu, JF, Yeh, TK, Wang, JC, Chang, CY, Chang, JY & Liou, JP 2014, 'Azaindolylsulfonamides, with a more selective inhibitory effect on histone deacetylase 6 activity, exhibit antitumor activity in colorectal cancer HCT116 cells', Journal of Medicinal Chemistry, vol. 57, no. 10, pp. 4009-4022. https://doi.org/10.1021/jm401899x

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

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.",

author = "Lee, {Hsueh Yun} and Tsai, {An Chi} and Chen, {Mei Chuan} and Shen, {Po Jung} and Cheng, {Yun Ching} and Kuo, {Ching Chuan} and Pan, {Shiow Lin} and Liu, {Yi Min} and Liu, {Jin Fen} and Yeh, {Teng Kuang} and Wang, {Jing Chi} and Chang, {Chi Yen} and Chang, {Jang Yang} and Liou, {Jing Ping}",

year = "2014",

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doi = "10.1021/jm401899x",

language = "English",

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pages = "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

AU - Liu, Yi Min

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

Y1 - 2014/5/22

N2 - 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.

AB - 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.

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

Abstract

ASJC Scopus subject areas

UN SDGs

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