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 | |
| Publication status | Published - May 22 2014 |
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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 journal › Article
}
TY - JOUR
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.
UR - http://www.scopus.com/inward/record.url?scp=84901263366&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84901263366&partnerID=8YFLogxK
U2 - 10.1021/jm401899x
DO - 10.1021/jm401899x
M3 - Article
C2 - 24766560
AN - SCOPUS:84901263366
VL - 57
SP - 4009
EP - 4022
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 10
ER -