Design, synthesis, and evaluation of novel ursolic acid derivatives as HIF-1α inhibitors with anticancer potential

Hypoxia-inducible factor-1 alpha (HIF-1 alpha), a key mediator in tumor metastasis and angiogenesis, is associated with poor patient prognosis and has been recognized as an important cancer drug target. In this work, four novel series of ursolic acid derivatives containing oxadiazole, triazolone, and piperazine moieties were designed, synthesized, and evaluated for anti-tumor activity as HIF-1 alpha inhibitors. The majority of the compounds showed an excellent ability to inhibit the expression of HIF-1 alpha. In particular, 11b inhibited HIF-1 alpha transcriptional activity under hypoxic conditions with IC50 = 36.9 mu M. The cytotoxicity of these compounds was also assessed in human colon cancer cell HCT116 cells by the 3-(4,5-dimethyl-2 -thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, and no compounds showed any appreciable cytotoxic activity (IC50 > 100 mu mol/L), which was lower than that of ursolic acid (IC50 = 23.8 mu mol/L). The mechanism of action of the representative compound 11b was also investigated. (C) 2017 Elsevier Inc. All rights reserved.