2-Oxoindoline-based hydroxamic acids: novel HDAC inhibitors with promising anticancer activity.

Histone deacetylase (HDAC) inhibitors are important epigenetic anticancer agents that regulate gene expression, induce cell cycle arrest, and promote apoptosis. In this study, a novel series of 2-oxoindoline-capped hydroxamic acids was designed, synthesized and evaluated for their capacity to inhibit histone deacetylases and suppress cancer cell proliferation. The screening panel incorporated multiple cancer models spanning different organ systems, including colorectal adenocarcinoma (SW620, HCT116), triple-negative breast cancer (MDA-MB-231), non-small cell lung carcinoma (A549), and prostate cancer (PC-3). Comparative assessment against non-transformed fibroblasts (MRC-5) enabled evaluation of selectivity and tolerability profiles. Several derivatives exhibited potent HDAC inhibition at submicromolar concentrations, with compounds 7c, 10b, and 10c showing stronger activity than the reference inhibitor SAHA. Among them, compound 10c demonstrated broad antiproliferative effects while maintaining relatively low toxicity toward normal cells. Mechanistic investigations revealed that 10c induced S-phase cell cycle arrest and promoted apoptosis in SW620 colorectal cancer cells. Molecular docking studies against multiple HDAC isoforms supported the experimental findings by revealing favorable zinc coordination and key interactions within the catalytic pocket. To further elucidate the binding behavior and dynamic features of the most active derivatives, molecular dynamics simulations were performed for HDAC complexes with 7c, 10b, and 10c. The simulations revealed stable protein-ligand interactions without perturbation of the overall protein structure, while highlighting distinct binding dynamics among the compounds, with 10c exhibiting the highest binding persistence, followed by 7c and 10b. In addition,