Developing multitarget coumarin based anti-breast cancer agents: synthesis and molecular modeling study

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Cancer Biology

Background:

• Breast cancer remains a leading cause of cancer-related mortality worldwide.
• Developing novel therapeutics with improved efficacy and selectivity is crucial for combating breast cancer.
• Coumarin scaffolds represent a versatile platform for the design of potential anti-cancer agents.

Purpose of the Study:

• Synthesize and evaluate novel 7-substituted coumarin derivatives with a C4-methyl ester moiety.
• Assess the in vitro anti-proliferative activity against human breast cancer cell lines (MCF-7 and MDA-MB-231).
• Investigate the inhibitory potential against epidermal growth factor receptor (EGFR) and aromatase (ARO) enzymes.

Main Methods:

• Chemical synthesis of 7-substituted coumarin scaffolds.
• In vitro anti-proliferative assays using Doxorubicin (DOX) as a reference.
• Enzyme inhibition assays with erlotinib and exemestane (EXM) as standards.
• Cell cycle analysis, apoptosis induction studies, and mechanistic pathway investigation (caspase-9, Bax/Bcl-2 ratio).
• In silico studies including molecular docking, ADMET screening, and Quantitative Structure-Activity Relationship (QSAR).

Main Results:

• Compounds 2 and 8 demonstrated significant selectivity against MCF-7 cells.
• Compounds 10, 12, and 14 showed considerable selectivity against Estrogen Receptor-negative cells.
• Compound 8 exhibited potent aromatase inhibition, while compounds 10 and 12 showed strong EGFR inhibitory activity.
• Promising compounds induced cell cycle arrest at G0-G1 and S phases and promoted apoptosis.
• Mechanistic studies confirmed apoptosis induction via elevated caspase-9 and Bax/Bcl-2 ratio.
• In silico analyses supported the potential therapeutic applications of the synthesized compounds.

Conclusions:

• The synthesized 7-substituted coumarin derivatives possess significant in vitro anti-proliferative and enzyme inhibitory activities against breast cancer.
• Compounds 8, 10, and 12 are identified as lead candidates for further development as anti-cancer therapeutics.
• The observed anti-cancer effects are mediated through cell cycle arrest and apoptosis induction.
• The combination of in vitro and in silico findings provides a strong foundation for the clinical translation of these novel coumarin-based agents.