Flavothione‐3‐carboxylate Derivatives: Synthesis, Molecular Docking, and Antiproliferative Activity against Breast Cancer

Abstract

AbstractThis study explores the potential of Flavothione‐3‐Carboxylate derivatives as inhibitors of glycogen synthase kinase 3 beta (GSK‐3β) for the treatment of breast cancer. GSK‐3β plays a critical role in cancer cell survival, proliferation, and chemotherapy resistance. Inhibitors of GSK‐3β have emerged as promising candidates for developing new cancer therapies. Flavatione‐3‐carboxylate derivatives were synthesized in a single step through a three‐component reaction using 4‐hydroxycoumarin, 2‐nitrovinylbenzene, and alcohol, catalyzed by 4‐dimethylaminopyridine. The reaction was followed by treatment with Lawson's reagent in toluene solvent. The structures of these derivatives were elucidated by infrared (IR), nuclear magnetic resonance (NMR), and mass spectrometry (MS). Their drug‐likeness was assessed using the SwissADME tool. The antiproliferative activity of the synthesized compound was evaluated on estrogen‐dependent MCF‐7 and non‐estrogen‐dependent MDA‐MB‐231 breast cancer cell lines. Among the tested compounds, NS16 demonstrated significant antiproliferative activity with an IC50 value of 5.69±1 μM against MCF‐7 ER+ cells, while NS04, NS05, NS07, and NS08 showed efficacy against MDA‐MB‐231 ER‐ cells with IC50 values ranging from 4.56±1 to 7.07±1 μM. Furthermore, the GSK‐3β activity assay revealed potent inhibitory effects of nitrophenyl and halo‐phenyl Flavothiones‐3‐Carboxylate derivatives on GSK‐3β activity. However, compounds NS15 and NS16 exhibited lower efficacy in inhibiting the enzyme, despite their anticancer activity.