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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