Synthesis and evaluation of 3-(phenylethynyl)-1,1′-biphenyl-2-carboxylate derivatives as new HIF-1 inhibitors

Selaginellins are a type of rare natural products from the genus Selaginella with unusual alkynyl phenol skeletons and extensive biological activities. Previous structural simplification of these natural compounds afforded a series of diaryl acetylene derivatives with hypoxia-inducible factor 1 (HIF-1) inhibitory activity. In this study, we synthesized thirty compounds by stepwise optimization using methyl 3-(4-methoxylphenyl ethynyl)-[4'-methoxyl-1,1'-biphenyl]-2-carboxylate (1a) as a lead compound and evaluated their HIF-1 inhibitory activity by dual luciferase reporter assay. Among them, compound 9i displayed the most potent HIF-1 inhibitory activity (IC50 = 1.5 +/- 0.03 mu M) with relatively low cytotoxicity. Under hypoxia, compound 9i showed no effect on the accumulation of HIF-1 alpha protein in western blot analysis, but could down-regulate the expression of VEGF mRNA, the downstream target gene of HIF-1 pathway. Cell-based activity assay demonstrated that compound 9i could inhibit the hypoxia-induced migration, invasion and proliferation of HeLa cells at the concentrations of 1 similar to 5 mu M. In mouse breast cancer xenograft model, compound 9i exhibited obvious tumor growth inhibition and very low toxicity at a dose of 15 mg/kg. The results suggested that compound 9i would be a potential antitumor agent via HIF-1 pathway inhibition.

Automated summary

In this study, a series of compounds were synthesized with compound 9i showing potent HIF-1 inhibitory activity and potential as an antitumor agent. It effectively suppressed tumor cell growth and migration, demonstrating significant inhibition in a mouse breast cancer model.