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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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.",
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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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