Quinoline/Pyrido-Pyrimidine Derivatives as Tubulin Polymerization Inhibitors: Design, Synthesis, Computational, and...

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Computational Chemistry

Background:

• Breast and colon cancers are major global health concerns.
• Quinoline/pyrido[2,3-d]pyrimidin-4(3H)-one derivatives are promising anticancer agents.
• Targeting tubulin polymerization is a validated anticancer strategy.

Purpose of the Study:

• Synthesize and characterize novel quinoline/pyrido[2,3-d]pyrimidin-4(3H)-one derivatives.
• Evaluate their antiproliferative and tubulin polymerization inhibitory activities.
• Identify structure-activity relationships for enhanced anticancer efficacy.

Main Methods:

• Spectroscopic techniques (1H NMR, 13C NMR, IR, MS) for characterization.
• Density Functional Theory (DFT) for computational analysis.
• In vitro assays against MCF-7, MDA-MB-231, HCT-116 cancer cell lines and HEK-293 normal cells.
• Molecular docking and dynamics simulations.

Main Results:

• A series of quinoline/pyrido[2,3-d]pyrimidin-4(3H)-one derivatives were successfully synthesized and characterized.
• Compound 4g exhibited potent antiproliferative activity (IC50 = 3.02 ± 0.63 μM against MCF-7) and significant tubulin polymerization inhibition.
• Selective anticancer activity was observed, with minimal cytotoxicity against normal HEK-293 cells.
• Structure-activity relationship studies highlighted the importance of methoxy-substituted phenyl and cycloheptane moieties.

Conclusions:

• The synthesized quinoline/pyrido[2,3-d]pyrimidin-4(3H)-one derivatives possess selective anticancer potential.
• Compound 4g is a promising lead candidate for further development as an anticancer therapeutic.
• Molecular modeling studies support the drug-like behavior and mechanism of action of compound 4g.