Discovery and optimization of new benzofuran derivatives against p53-independent malignant cancer cells through inhibition of HIF-1 pathway

Bioorg Med Chem Lett. 2016 Jun 1;26(11):2713-8. doi: 10.1016/j.bmcl.2016.03.112. Epub 2016 Apr 1.

Abstract

p53-independent malignant cancer is still severe health problem of human beings. HIF-1 pathway is believed to play an important role in the survival and developing progress of such cancers. In the present study, with the aim to inhibit the proliferation of p53-independent malignant cells, we disclose the optimization of 6a, the starting compound which is discovered in the screening of in-house compound collection. The structure-activity relationship (SAR) is summarized. The most potent derivative 8d, inhibits the proliferation of both p53-null and p53-mutated cells through inhibition of HIF-1 pathway. Our findings here provide a new chemotype in designing potent anticancer agent especially against those p53-independent malignant tumors.

Keywords: Antitumor; Apoptosis; Benzofuran; Cycle arrest; HIF-1 inhibition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / pharmacology*
  • Benzofurans / chemical synthesis
  • Benzofurans / chemistry
  • Benzofurans / pharmacology*
  • Cell Cycle Checkpoints / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Drug Screening Assays, Antitumor
  • HCT116 Cells
  • Humans
  • Hypoxia-Inducible Factor 1 / antagonists & inhibitors*
  • MCF-7 Cells
  • Molecular Structure
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Structure-Activity Relationship
  • Tumor Suppressor Protein p53 / antagonists & inhibitors*
  • Tumor Suppressor Protein p53 / deficiency

Substances

  • Antineoplastic Agents
  • Benzofurans
  • Hypoxia-Inducible Factor 1
  • Tumor Suppressor Protein p53
  • benzofuran