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Medicinal Chemistry


ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

Novel 3-substituted-2-oxoindoline-based N-hydroxypropenamides as Histone Deacetylase Inhibitors and Antitumor Agents

Author(s): Do T. M. Dung, Phan T. P. Dung, Dao T. K. Oanh, Pham T. Hai, Le T. T. Huong, Vu D. Loi, Hyunggu Hahn, Byung W. Han, Jisung Kim, Sang-Bae Han and Nguyen-Hai Nam

Volume 11, Issue 8, 2015

Page: [725 - 735] Pages: 11

DOI: 10.2174/1573406411666150702130633

Price: $65


Histone deacetylases (HDAC) are currently a group of validated targets for anticancer drug discovery and development. In our research program to find novel small molecules targeting these enzymes, we designed and synthesized two series of 3-hydroxyimino-2-oxoindoline- and 3- methoxyimino-2-oxoindoline-based N-hydroxypropenamides (3a-g, 6a-g). The results show that these propenamides potently inhibited HDAC2 with IC50 values in sub-micromolar range, approximately 10-fold lower than that of SAHA (also known as suberoylanilohydroxamic acid). Evaluation of cytotoxicity of these compounds in three human cancer cell lines revealed that most of the synthesized compounds were up to 5-fold more cytotoxic than SAHA. Docking studies showed that the compounds bound to HDAC2 at the binding site with higher binding affinities compared to SAHA. Our present results demonstrate that these novel 3-substituted-2-oxoindoline-based N-hydroxypropenamides are potential for further development as anticancer agents.

Keywords: Histone deacetylase (HDAC) inhibitors, hydroxamic acids, 3-substituted-2-oxoindoline, propenamide.

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