Design, synthesis, and biological evaluation of cycloarylchalcone derivatives as microtubule inhibitors targeting breast cancer cells.

AIM: The increasing burden of breast cancer and drug resistance highlights the need for new chemotherapeutic agents. This study aimed to design and evaluate novel cycloarylchalcone derivatives as potential anticancer candidates targeting microtubules.

MATERIALS & METHODS: A series of cycloarylchalcone derivatives containing a cyclohexenone core (CY1-10) were synthesized via Claisen-Schmidt condensation followed by Michael addition. Structural variations at the R and R1 positions were introduced to optimize activity. The cytotoxicity of the compounds was evaluated against MCF-7 and MDA-MB-231 breast cancer cell lines using the MTT assay, with colchicine as the reference drug. Molecular docking was performed using Schrödinger Maestro against the tubulin colchicine-binding site (PDB ID: 1SA0). ADME and toxicity profiles were also assessed.

RESULTS: Compound CY2 demonstrated the most potent cytotoxicity with IC50 values of 4.34 ± 0.37 µM (MCF-7) and 5.19 ± 0.26 µM (MDA-MB-231). Electron-donating substituents at both R and R1 positions enhanced activity. CY1 exhibited the best docking score (-7.506 kcal/mol) with key interactions at CYS241. ADME screening suggested good oral bioavailability, and compounds displayed acceptable toxicity (LD50 = 860-2000 mg/kg).

CONCLUSIONS: Cycloarylchalcone derivatives exhibited promising anticancer activity and represent potential leads for further preclinical development.