Design, synthesis, and evaluation of novel Indole-Based small molecules as sirtuin inhibitors with anticancer...

Area of Science:

• Oncology
• Medicinal Chemistry
• Biochemistry

Background:

• Hepatocellular carcinoma (HCC) is a major global cause of cancer mortality.
• Chronic infections and metabolic disorders are key drivers of HCC.
• Sirtuins, especially SIRT1, play a critical role in HCC development, presenting a therapeutic target.

Purpose of the Study:

• To design and synthesize novel indole-based small molecules.
• To evaluate their sirtuin inhibitory potential and anticancer activity against HCC cell lines.

Main Methods:

• Structure-activity relationship (SAR) analysis guided the selection of four lead compounds (4g, 4h, 4o, 7j).
• Drug-target interaction (DTI) predictions using DEEPScreen and molecular docking studies were performed.
• In vitro assays assessed sirtuin activity inhibition, cell cycle arrest, and apoptosis induction.

Main Results:

• Compounds 4o, 4g, and 7j showed potent interactions with SIRT1, as predicted by DTI and docking.
• Compound 4g exhibited the highest in vitro sirtuin activity inhibition.
• Compound 4g induced G1 cell cycle arrest and apoptosis in HCC cell lines.

Conclusions:

• Novel indole derivatives effectively inhibit sirtuins and display anticancer properties against HCC.
• Compound 4g is a promising candidate for further development as an HCC therapeutic agent.
• Targeting sirtuins with indole-based molecules represents a viable strategy for HCC treatment.