Design, Synthesis and Biological Evaluation of Novel HIF1α Inhibitors

Anticancer Res. 2015 Jul;35(7):3849-59.

Abstract

Elevated levels of hypoxia inducible factor-1 (HIF1) are linked to tumor metastasis, angiogenesis, poor patient prognosis and response to chemotherapy. HIF1α is a master regulator of the hypoxic response, including in cancer cells, through transcriptional activation of several target genes. Previously, we identified compound CJ-3k with high anti-HIF1α activity based on the structure of a well-known HIF1α inhibitor, YC-1. In this study, the CJ-3k scaffold was systematically modified to explore the structure-activity relationships. Fifty-three new CJ-3k analogs were synthesized and screened for their anti-HIF-1α activity in a luciferase-transfected human breast cancer cell line (MDA-MB-231). Some of these new analogs have a significantly greater activity than that of CJ-3k and hold potential for development as new therapeutic agents for the treatment of cancer.

Keywords: HIF-1α inhibitors; Hypoxia; benzimidazoles; breast cancer.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology*
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / metabolism
  • Cell Line, Tumor
  • Female
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors*
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit