Azaindolylsulfonamides, with a more selective inhibitory effect on histone deacetylase 6 activity, exhibit antitumor activity in colorectal cancer HCT116 cells.
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.
School of Pharmacy, College of Pharmacy, Taipei Medical University , 250 Wuxing Street, Taipei 11031, Taiwan.
Hsueh-Yun
HY
Lee
An-Chi
AC
Tsai
Mei-Chuan
MC
Chen
Po-Jung
PJ
Shen
Yun-Ching
YC
Cheng
Ching-Chuan
CC
Kuo
Shiow-Lin
SL
Pan
Yi-Min
YM
Liu
Jin-Fen
JF
Liu
Teng-Kuang
TK
Yeh
Jing-Chi
JC
Wang
Chi-Yen
CY
Chang
Jang-Yang
JY
Chang
Jing-Ping
JP
Liou
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D005260:Female; D045325:HCT116 Cells; D057809:HEK293 Cells; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008813:Mice, Inbred ICR; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D013449:Sulfonamides; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases