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.
ASJC Scopus subject areas
- Molecular Medicine
- Drug Discovery
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