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

Area of Science:

• Medicinal Chemistry
• Epigenetics
• Cancer Biology

Background:

• Histone deacetylase (HDAC) inhibitors are crucial epigenetic anticancer agents.
• They regulate gene expression, cell cycle arrest, and apoptosis.
• Novel HDAC inhibitors are needed to overcome resistance and improve therapeutic outcomes.

Purpose of the Study:

• Design, synthesize, and evaluate novel 2-oxoindoline-capped hydroxamic acids as HDAC inhibitors.
• Assess their antiproliferative activity across various cancer models.
• Investigate the mechanism of action and binding interactions of potent derivatives.

Main Methods:

• Synthesis of 2-oxoindoline-capped hydroxamic acids.
• In vitro enzymatic assays for HDAC inhibition.
• Antiproliferative assays using diverse cancer cell lines (e.g., SW620, HCT116, MDA-MB-231, A549, PC-3) and normal fibroblasts (MRC-5).
• Cell cycle analysis and apoptosis assays.
• Molecular docking and molecular dynamics simulations.
• In silico ADME/Toxicity predictions.

Main Results:

• Several synthesized derivatives exhibited potent submicromolar HDAC inhibition.
• Compounds 7c, 10b, and 10c outperformed the reference SAHA in activity.
• Compound 10c demonstrated broad-spectrum antiproliferative effects with favorable selectivity against normal cells.
• 10c induced S-phase arrest and apoptosis in SW620 cells.
• Molecular modeling confirmed favorable binding interactions and stable dynamics for 10c.
• In silico predictions suggested acceptable drug-like properties and safety for 10c.

Conclusions:

• 2-oxoindoline-based hydroxamic acids are promising scaffolds for HDAC-targeted anticancer drug development.
• Compound 10c shows significant potential as a lead compound due to its potent activity, broad spectrum, and favorable safety profile.
• Further optimization of these compounds may lead to novel epigenetic therapies for various cancers.