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

Veronica Di Paolo, Chiara Fulci, Dante Rotili, Francesca Sciarretta, Alessia Lucidi, Blasco Morozzo Della Rocca, Anastasia De Luca, Antonio Rosato, Luigi Quintieri, Anna Maria Caccuri

Research output: Contribution to journalArticlepeer-review

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 In an effort to improve the metabolic stability of 3, its ester group has been replaced by an amide, leading to N-(6-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)thio)hexyl)benzamide (4).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.

Original languageEnglish
Pages (from-to)1131-1139
Number of pages9
JournalJournal of Enzyme Inhibition and Medicinal Chemistry
Volume34
Issue number1
DOIs
Publication statusPublished - Dec 2019

Keywords

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

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