Synthesis and biological evaluation of oxazinonaphthalene-3-one derivatives as potential anticancer agents and tubulin inhibitors

Objective(s): In the present study, a new series of oxazinonaphthalene-3-one analogs was designed and synthesized as novel tubulin inhibitors. Materials and Methods: The cytotoxic activity of the synthesized compounds was evaluated against four human cancer cell lines including A2780 (human ovarian carcinoma), A2780/RCIS (cisplatin resistant human ovarian carcinoma), MCF-7 (human breast cancer cells), and MCF-7/MX (mitoxantrone resistant human breast cancer cells), those compounds which demonstrated the most antiproliferative activity in the MTT test were selected to investigate their tubulin inhibition activity and their effects on cell cycle arrest (at the G2/M phase). Moreover, molecular docking studies of the selected compounds in the catalytic site of tubulin (PDB ID: 4O2B) were carried out to describe the results of biological experiments. Results: Most of our compounds exhibited significant to moderate cytotoxic activity against four human cancer cell lines. Among them, Compounds 4d, 5c, and 5g, possessing trimethoxy phenyl, showed the most antiproliferative activity with IC50 values ranging from 4.47 to 52.8 μM. Conclusion: The flow cytometric analysis of A2780 cancer cell line treated with compounds 4d, 5c, and 5g showed that these compounds induced cell cycle arrest at the G2/M phase. Compound 5g, the most antiproliferative compound, inhibited tubulin polymerization in a dose-dependent manner. Molecular docking studies of 5g into the colchicine-binding site of tubulin displayed a possible mode of interaction between this compound and tubulin.

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