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

Bioorg Chem. 2017 Dec:75:157-169. doi: 10.1016/j.bioorg.2017.09.013. Epub 2017 Sep 20.

Abstract

Hypoxia-inducible factor-1α (HIF-1α), 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-1α inhibitors. The majority of the compounds showed an excellent ability to inhibit the expression of HIF-1α. In particular, 11b inhibited HIF-1α transcriptional activity under hypoxic conditions with IC50=36.9μM. 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>100μmol/L), which was lower than that of ursolic acid (IC50=23.8μmol/L). The mechanism of action of the representative compound 11b was also investigated.

Keywords: Anticancer activity; Cell proliferation; Cytotoxicity; HIF-1α inhibitor; Ursolic acid derivatives.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology
  • Cell Cycle Checkpoints / drug effects
  • Cell Hypoxia
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Drug Design*
  • Drug Evaluation, Preclinical
  • HCT116 Cells
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors*
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Inhibitory Concentration 50
  • Structure-Activity Relationship
  • Transcription, Genetic / drug effects
  • Triterpenes / chemical synthesis*
  • Triterpenes / chemistry*
  • Triterpenes / metabolism
  • Triterpenes / pharmacology
  • Ursolic Acid
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • (5-oxo-4-phenyl-4,5-dihydro-1H-1,2,4-triazol-1-yl)propyl-3-hydroxy-urs-12-en-28-oate
  • Antineoplastic Agents
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Triterpenes
  • Vascular Endothelial Growth Factor A