Development of new anticancer thiadiazole-sulfonamides as dual EGFR/carbonic anhydrase inhibitors

Area of Science:

• Medicinal Chemistry
• Oncology
• Molecular Biology

Background:

• Cancer cells often overexpress epidermal growth factor receptor (EGFR) and carbonic anhydrase IX (CA-IX).
• Targeting both EGFR and CA-IX simultaneously offers a potential strategy for selective anticancer drug development.
• Thiadiazole-sulfonamide scaffolds are explored for their potential as dual inhibitors.

Purpose of the Study:

• To synthesize novel thiadiazole-sulfonamide derivatives as dual inhibitors of EGFR and CA-IX.
• To evaluate the synthesized compounds for selective anticancer activity against breast cancer cell lines.
• To investigate the mechanism of action, including apoptosis induction and cell cycle effects.

Main Methods:

• Synthesis of thiadiazole-sulfonamide derivatives.
• In vitro cytotoxicity assays against MDA-MB-231, MCF-7, and Vero cell lines.
• Enzymatic inhibition assays for EGFR and CA-IX.
• Apoptosis assessment via gene expression (BAX/Bcl-2, caspases) and flow cytometry.
• Molecular docking, molecular dynamics simulations, DFT calculations, and in silico ADMET predictions.

Main Results:

• Compound 14 demonstrated potent cytotoxicity against breast cancer cells (MDA-MB-231, MCF-7) with high selectivity over normal Vero cells.
• Compound 14 effectively inhibited both EGFR and CA-IX enzymes, outperforming reference drugs.
• Apoptosis was induced, evidenced by increased BAX/Bcl-2 ratio, caspase activation, and G1-phase cell cycle arrest.
• Computational studies confirmed stable binding interactions and favorable pharmacokinetic properties.

Conclusions:

• Compound 14 is a promising dual EGFR/CA-IX inhibitor with selective anticancer properties.
• The findings support further investigation of Compound 14 for in vivo anticancer efficacy.
• Thiadiazole-sulfonamide derivatives represent a viable class for developing targeted cancer therapies.