Design, synthesis, molecular modeling, and biological evaluation of pyrazole-naphthalene derivatives as potential anticancer agents on MCF-7 breast cancer cells by inhibiting tubulin polymerization

A new series of pyrazole-naphthalene derivatives (5a-5q) have been synthesized and evaluated for their anticancer activity against human breast cancer cell lines (MCF-7). Most of newly synthesized compounds (except 5i, 5m, and 5p) exhibited potent antiproliferative activity in the range of IC₅₀ = 2.78 ± 0.24 μM - 9.13 ± 0.47 μM. Among them, compound 5j (IC₅₀ = 2.78 ± 0.24 μM), bearing ethoxy at the 4-position of the phenyl ring, was found to be the most active compound in this series of compounds, with five folds more active than the standard drug cisplatin (IC₅₀ = 15.24 ± 1.27 μM). In addition, compound 5j and colchicine showed the same ability to inhibit tubulin polymerization with the IC₅₀ values of 4.6 μM and 6.7 μM, respectively. Cellular mechanism studies elucidated that compound 5j arrested the cell cycle at G2/M phase and induced apoptosis. Furthermore, molecular docking analysis revealed that compound 5j formed stable interactions in the colchicine-binding site of tubulin.

Keywords: Anticancer; Naphthalene; Pyrazole; Tubulin polymerization inhibitor.