Synthesis and characterisation of a new benzamide-containing nitrobenzoxadiazole as a GSTP1-1 inhibitor endowed with high stability to metabolic hydrolysis

J Enzyme Inhib Med Chem. 2019 Dec;34(1):1131-1139. doi: 10.1080/14756366.2019.1617287.

Abstract

The antitumor agent 6-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)thio)hexan-1-ol (1) is a potent inhibitor of GSTP1-1, a glutathione S-transferase capable of inhibiting apoptosis by binding to JNK1 and TRAF2. We recently demonstrated that, unlike its parent compound, the benzoyl ester of 1 (compound 3) exhibits negligible reactivity towards GSH, and has a different mode of interaction with GSTP1-1. Unfortunately, 3 is susceptible to rapid metabolic hydrolysis. In an effort to improve the metabolic stability of 3, its ester group has been replaced by an amide, leading to N-(6-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)thio)hexyl)benzamide (4). Unlike 3, compound 4 was stable to human liver microsomal carboxylesterases, but retained the ability to disrupt the interaction between GSTP1-1 and TRAF2 regardless of GSH levels. Moreover, 4 exhibited both a higher stability in the presence of GSH and a greater cytotoxicity towards cultured A375 melanoma cells, in comparison with 1 and its analog 2. These findings suggest that 4 deserves further preclinical testing.

Keywords: A375 human melanoma; GSTP1-1; Nitrobenzoxadiazoles; TRAF2; glutathione.

MeSH terms

  • 4-Chloro-7-nitrobenzofurazan / chemical synthesis
  • 4-Chloro-7-nitrobenzofurazan / chemistry
  • 4-Chloro-7-nitrobenzofurazan / pharmacology*
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Benzamides / chemistry
  • Benzamides / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Glutathione S-Transferase pi / antagonists & inhibitors*
  • Glutathione S-Transferase pi / metabolism
  • Humans
  • Hydrolysis
  • Models, Molecular
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Benzamides
  • Enzyme Inhibitors
  • benzamide
  • Glutathione S-Transferase pi
  • 4-Chloro-7-nitrobenzofurazan

Grants and funding

Our work was supported in part by Italian Association for Cancer Research (AIRC) [Grant IG-21354] to A.R. and by “Budget Integrato per la Ricerca dei Dipartimenti (BIRD) 2018” grant of the University of Padova to A.R.