Discovery of 3-phenylquinolinylchalcone derivatives as potent and selective anticancer agents against breast cancers

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Cancer Research

Background:

• Breast cancer remains a leading cause of cancer-related deaths globally.
• Developing novel therapeutic agents with improved efficacy and reduced toxicity is crucial.
• Chalcone derivatives have emerged as a promising class of compounds with diverse biological activities.

Purpose of the Study:

• To synthesize and evaluate novel 3-phenylquinolinylchalcone derivatives for antiproliferative activity against breast cancer.
• To identify a lead compound for further mechanistic studies.
• To elucidate the mechanism of action of the most potent derivative.

Main Methods:

• Synthesis of 3-phenylquinolinylchalcone derivatives.
• In vitro antiproliferative assays against MCF-7, MDA-MB-231, and SKBR-3 breast cancer cell lines and H184B5F5/M10 normal cells.
• Flow cytometry for cell cycle analysis.
• Western blotting to assess protein expression (Bax, Bcl-2, PARP).
• Enzyme activity assays for caspase-3 and caspase-8.

Main Results:

• Compound 7, (E)-3-[3-(4-methoxyphenyl)quinolin-2-yl]-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one, exhibited significant antiproliferative activity (IC50 values 0.75-1.05 μM) against breast cancer cells with minimal toxicity to normal cells.
• Compound 7 inhibited tubulin polymerization and induced G2/M cell cycle arrest.
• Treatment with compound 7 led to apoptosis induction, evidenced by increased Bax, decreased Bcl-2, PARP cleavage, and activation of caspase-3 and -8.

Conclusions:

• Compound 7 is a potent antiproliferative agent against breast cancer cells.
• The mechanism involves tubulin polymerization inhibition, G2/M cell cycle arrest, and induction of apoptosis via caspase activation and PARP cleavage.
• Compound 7 represents a promising lead candidate for further development as a breast cancer therapeutic.