Design, synthesis and biological evaluation of novel hydroxamic acid-derived histone deacetylase inhibitors bearing a 2-oxoindoline scaffold as potential antitumor agents

Abstract

Histone deacetylases (HDACs) have emerged as compelling targets in developing anticancer therapeutics. This study outlines the development, synthesis, and biological evaluation of novel hydroxamic acid derivatives featuring a 2-oxoindoline scaffold, which exhibit high HDAC inhibitory activity and potential anticancer effects. Three series of N-hydroxycinnamamides, N-hydroxyheptanamides, and N-hydroxybenzamides were synthesized and assessed for their biological activity. The results of the biological activity evaluation indicated that the synthesized derivatives exhibited notable inhibitory effects against SW620 (colon cancer) and HCT116 (human colorectal carcinoma). Compound N-hydroxy-7-(2-oxoindolin-1-yl)heptanamide (6a) exhibited remarkable HDAC inhibitory activity, achieving sub-nanomolar potency with an IC₅₀ value of less than 0.001 µM. While this potent HDAC inhibition suggests strong enzymatic activity, the anticancer activity of 6a against SW620 and HCT116 was comparable to that of SAHA (IC₅₀ of 0.101 µM). Analysis of selected compound 6a also revealed that this compound effectively triggered both early and late stages of apoptosis and caused cell cycle arrest at the G2/M phase in SW620 cells. Finally, docking studies and molecular dynamics study conducted on the HDAC isoforms for series 6a-e identified key structural features that play a significant role in the inhibitory activity of the synthesized compounds.