Exploring the newer oxadiazoles as real inhibitors of human SIRT2 in hepatocellular cancer cells

Bioorg Med Chem Lett. 2020 Aug 15;30(16):127330. doi: 10.1016/j.bmcl.2020.127330. Epub 2020 Jun 11.

Abstract

A novel series of indazole tethered oxadiazoles (OTDs) derivatives were synthesized, characterized and screened for their anti-proliferative activity against hepatocellular carcinoma (HCC) cells. OTDs structure was further confirmed by Single-crystal X-ray diffraction studies. Among the tested OTDs, compound 2-(4-methoxyphenyl)-5-(1-methyl-1H-indazol-3-yl)-1,3,4-oxadiazole was found to inhibit the catalytical activity of SIRT2 and brings about apoptosis as shown by western blot analysis and flow cytometry data. Also, the tested OTDs were found to interact with the active site of human SIRT2 in silico but not with the cavity of co-crystal ligand 5-(3- hydroxypropyl)-3-(4-chlorophenyl)-1,2,4-oxadiazole, which indicate that these OTDs has potential in the development of SIRT2 inhibitors in liver cancer models.

Keywords: Drug-discovery; HCC; Indazole; Oxadiazole; SIRT2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Molecular Structure
  • Oxadiazoles / chemical synthesis
  • Oxadiazoles / chemistry
  • Oxadiazoles / pharmacology*
  • Sirtuin 2 / antagonists & inhibitors*
  • Sirtuin 2 / metabolism
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Oxadiazoles
  • SIRT2 protein, human
  • Sirtuin 2