Synthesis and biological evaluation of N-substituted 3-oxo-1,2,3,4-tetrahydro-quinoxaline-6-carboxylic acid derivatives as tubulin polymerization inhibitors

Abstract

A series of novel N-substituted 3-oxo-1,2,3,4-tetrahydro-quinoxaline-6-carboxy- lic acid derivatives were synthesized and evaluated for their biological activities. Among all synthesized target compounds, 13d exhibited the most potent antiproliferative activity against HeLa, SMMC-7721, K562 cell line (IC₅₀ = 0.126 μM, 0.071 μM, 0.164 μM, respectively). Furthermore, compound 13d inhibited tubulin polymerization (IC₅₀ = 3.97 μM), arrested cell cycle at the G2/M phase and induced apoptosis. The binding mode at the colchicine binding site was also probed. These studies provided a new molecular scaffold for the further development of antitumor agents that target tubulin.

Keywords: 3-Oxo-1,2,3,4-tetrahydro-quinoxaline-6-carboxylic acid derivatives; Antiproliferative; Cell apoptosis; Cell cycle analysis; Tubulin polymerization inhibitors.