Design, synthesis, and anticancer evaluation of benzophenone derivatives bearing naphthalene moiety as novel tubulin polymerization inhibitors

Abstract

A series of benzophenone derivatives bearing naphthalene moiety were designed, synthesized, characterized by ¹H NMR, ¹³C NMR, and HRMS and evaluated for their antiproliferative activity against human breast cancer cell line (MCF-7). Most of the tested derivatives showed good to moderate cytotoxicity against MCF-7 cell line. Among them, compound 4u (IC₅₀ = 1.47 ± 0.14 μM) was found to be the most active compound, which is more active than the standard drug cisplatin (IC₅₀ = 15.24 ± 1.27 μM). In vitro tubulin polymerization inhibition assay, EBI competition assay, cell cycle analysis, and cell apoptosis assay identified that compound 4u was a new tubulin polymerization inhibitor by targeting the colchicine binding site. Besides, molecular docking study showed that compound 4u has high binding affinities with the colchicine binding site of tubulin through hydrogen bond, cation-π, and hydrophobic interaction.

Keywords: Anticancer activity; Benzophenone; Naphthalene; Tubulin polymerization inhibitors.