Design and synthesis of novel quinoline-chalcone derivatives as dual inhibitors of tubulin polymerization and P-glycoprotein to overcome cisplatin resistance in cervical cancer
Cervical cancer remains a major cause of cancer death in women, often limited by cisplatin resistance. To overcome multidrug resistance (MDR), we designed and synthesized 23 novel quinoline-chalcone derivatives targeting both P-glycoprotein (P-gp) and the colchicine-binding site (CBS) of tubulin. Among them, compound 6h exhibited the most potent anti-proliferative activity against both cisplatin-sensitive HeLa cells (IC₅₀ = 6.69 μM) and cisplatin-resistant HeLa/DDP cells (IC₅₀ = 7.21 μM). The potency of compound 6h was superior than cisplatin (HeLa: 15.54 μM; HeLa/DDP: 94.32 μM) while displaying lower cytotoxicity towards normal cervical cells than cisplatin. Compound 6h demonstrated lower cisplatin resistance index (RI) in the HeLa/DDP cells than verapamil (RI: 1.27 vs. 2.22). Mechanistic studies demonstrated that compound 6h inhibited tubulin polymerization and induced G₂/M arrest and apoptosis in both the cell lines. Compound 6h reversed MDR by inhibiting P-gp efflux function, as evidenced by rhodamine 123 accumulation in HeLa/DDP cells. Molecular docking and dynamics simulations provided structural insights, confirming stable binding of 6h to the tubulin CBS (ΔG = -12.4 kcal/mol) and the P-gp hydrophobic lumen (ΔG = -10.8 kcal/mol). Zebrafish acute toxicity assay results demonstrated that the safety profile of compound 6h (0 % mortality at 400 μM) was superior than cisplatin (16.7 % mortality rate at 8 μM). To the best of our knowledge, compound 6h is the first reported quinoline-chalcone derivative with dual functions: direct antitumor activity and reversal of P-gp-mediated cisplatin resistance. Our results suggest that compound 6h is a promising compound and represents a novel strategy for combating drug-resistant cervical cancer.