Development of chromone-thiazolidine-2,4-dione Knoevenagel conjugates as apoptosis inducing agents

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Cancer Research

Background:

• Overexpression of B-cell lymphoma 2 (Bcl-2) protein disrupts apoptosis, a common feature in many cancers.
• Targeting anti-apoptotic proteins is a key strategy for cancer therapy.

Purpose of the Study:

• To design and synthesize novel chromone-linked thiazolidinediones targeting Bcl-2.
• To evaluate the anti-cancer potential and mechanism of action of these compounds.

Main Methods:

• In vitro synthesis and characterization of chromone-linked thiazolidinediones.
• Cytotoxicity assays on various cancer cell lines and normal HEK cells.
• Apoptosis induction studies using DAPI, AO/EtBr, Annexin-V binding, and ROS generation assays.
• Western blot analysis for Bcl-2 protein expression.
• Molecular docking studies against Bcl-2 family proteins.

Main Results:

• Compounds 8a, 8k, 8l, and 8n exhibited significant anti-proliferative activity (IC50 < 10 µM).
• Compound 8l demonstrated potent cytotoxicity against A549 cells (IC50 = 6.1 µM) with notable selectivity.
• Compound 8l induced apoptosis, DNA damage, and increased ROS generation.
• Compound 8l significantly reduced Bcl-2 protein expression by 79.1%.
• Molecular docking suggested favorable interactions with Mcl-1, another Bcl-2 family member.

Conclusions:

• Chromone-linked thiazolidinediones are promising candidates for targeting Bcl-2 in cancer therapy.
• Compound 8l exhibits potent and selective anti-cancer activity through apoptosis induction.
• These compounds warrant further investigation as potential anti-cancer agents.