Synthesis of (aryloxyacetylamino)-isonicotinic/nicotinic acid analogues as potent hypoxia-inducible factor (HIF)-1α inhibitors

We report a new series of HIF-1α inhibitors which were obtained through structural modifications of previously reported lead 1. The in vitro inhibitory potencies of newly synthesized compounds were evaluated against hypoxia-induced HIF-1 activation using cell-based reporter assay in three human cancer cell lines including SK-Hep-1, Hep3B, and AGS cells. Several compounds displayed significant inhibitory activity in all the three tested cell lines. In particular, analogue 17 displayed potent inhibition of hypoxia-induced accumulation of HIF-1α protein in Hep3B cell line, in addition to the dose-dependent inhibition of HIF-1 target genes VEGF and EPO.