title: A new nitrobenzoxadiazole-based GSTP1-1 inhibitor with a previously unheard of mechanism of action and high stability.
abstract: BACKGROUND
  The nitrobezoxadiazole derivative NBDHEX is a potent inhibitor of glutathione transferase P1-1 (GSTP1-1) endowed with outstanding anticancer activity in different tumor models.
  
  
  OBJECTIVE
  To characterize by in vitro biochemical and in silico studies the NBDHEX analogues named MC2752 and MC2753.
  
  
  METHODS
  Synthesis of MC2752 and MC2753, biochemical assays and in silico docking and normal-mode analyses.
  
  
  RESULTS
  The presence of a hydrophobic moiety in the side chain of MC2753 confers unique features to this molecule. Unlike its parent drug NBDHEX, MC2753 does not require GSH to trigger the dissociation of the complex between GSTP1-1 and TRAF2, and displays high stability towards the nucleophilic attack of the tripeptide under physiological conditions.
  
  
  CONCLUSIONS
  MC2753 may represent a lead compound for the development of novel GSTP1-1 inhibitors not affected in their anticancer action by fluctuations of cellular GSH levels, and characterized by an increased half-life in vivo.
authors.affiliation: a Department of Experimental Medicine and Surgery , University of Tor Vergata , Rome , Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Fulci
authors.affiliation: b Department of Drug Chemistry and Technologies , University of Rome "Sapienza" , Rome , Italy.
authors.forename: Dante
authors.initials: D
authors.lastname: Rotili
authors.affiliation: a Department of Experimental Medicine and Surgery , University of Tor Vergata , Rome , Italy.
authors.forename: Anastasia
authors.initials: A
authors.lastname: De Luca
authors.affiliation: c Department of Chemical Sciences and Technologies.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Stella
authors.affiliation: d Department of Biology , University of Tor Vergata , Rome , Italy.
authors.forename: Blasco
authors.initials: B
authors.lastname: Morozzo Della Rocca
authors.affiliation: b Department of Drug Chemistry and Technologies , University of Rome "Sapienza" , Rome , Italy.
authors.forename: Mariantonietta
authors.initials: M
authors.lastname: Forgione
authors.affiliation: e Department of Pharmaceutical and Pharmacological Sciences , University of Padova , Padova , Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Di Paolo
authors.affiliation: b Department of Drug Chemistry and Technologies , University of Rome "Sapienza" , Rome , Italy.|f Pasteur Institute, Cenci Bolognetti Foundation, University of Rome "La Sapienza" , Rome , Italy.
authors.forename: Antonello
authors.initials: A
authors.lastname: Mai
authors.affiliation: d Department of Biology , University of Tor Vergata , Rome , Italy.
authors.forename: Mattia
authors.initials: M
authors.lastname: Falconi
authors.affiliation: e Department of Pharmaceutical and Pharmacological Sciences , University of Padova , Padova , Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Quintieri
authors.affiliation: a Department of Experimental Medicine and Surgery , University of Tor Vergata , Rome , Italy.|g The NAST Centre for Nanoscience & Nanotechnology & Innovative Instrumentation, University of Tor Vergata , Rome , Italy.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Caccuri
mesh_terms: D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D051549:Glutathione S-Transferase pi / Q000037:antagonists & inhibitors*; D006801:Humans; D008958:Models, Molecular; D010080:Oxazoles / Q000737:chemistry / Q000494:pharmacology*; D013050:Spectrometry, Fluorescence; D013056:Spectrophotometry, Ultraviolet
chemical_list: D004791:Enzyme Inhibitors; D010080:Oxazoles; D051549:Glutathione S-Transferase pi
keywords: GSH; GSTP1-1; NBDHEX; TRAF2; nitrobenzoxadiazoles