Chroman-4-one- and chromone-based sirtuin 2 inhibitors with antiproliferative properties in cancer cells

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Pharmacology

Background:

• Sirtuins (SIRTs) are NAD(+)-dependent deacetylases implicated in aging and diseases.
• SIRT2 is a key target for therapeutic intervention due to its role in inflammation and aging-associated pathologies.
• Previous research identified chroman-4-ones as effective SIRT2 inhibitors.

Purpose of the Study:

• To design and synthesize novel chroman-4-one and chromone-based compounds targeting SIRT2.
• To evaluate the inhibitory potency and selectivity of these new compounds against SIRT2.
• To assess the antiproliferative activity and mechanism of action in cancer cell lines.

Main Methods:

• Synthesis of novel chroman-4-one and chromone derivatives with diverse heterofunctionalities.
• Enzyme inhibition assays to determine SIRT2 inhibitory activity and selectivity.
• Cell-based assays using MCF-7 (breast cancer) and A549 (lung carcinoma) cell lines.
• Western blot analysis to measure α-tubulin acetylation levels.
• Homology modeling to predict inhibitor binding modes.

Main Results:

• Novel chroman-4-one and chromone derivatives exhibited potent and selective SIRT2 inhibition.
• The synthesized compounds maintained high inhibitory activity and selectivity.
• Two compounds demonstrated significant antiproliferative effects in both breast cancer and lung carcinoma cell lines.
• Increased α-tubulin acetylation in treated cells confirmed SIRT2 inhibition.
• A plausible binding mode for the inhibitors was proposed based on homology modeling and structure-activity relationship (SAR) data.

Conclusions:

• The developed chroman-4-one and chromone derivatives are potent and selective SIRT2 inhibitors.
• These compounds exhibit promising antiproliferative activity against cancer cells, likely mediated through SIRT2 inhibition.
• The findings support the therapeutic potential of targeting SIRT2 in cancer treatment.
• The proposed binding mode provides insights for further optimization of SIRT2 inhibitors.