title: Synthesis and study of 2-(pyrrolesulfonylmethyl)-N-arylimines: a new class of inhibitors for human glutathione transferase A1-1.
abstract: Overexpression of human GSTA1-1 in tumor cells is part of MDR mechanisms. We report on the synthesis of 11 pyrrole derivatives as hGSTA1-1 inhibitors starting from 1-methyl-2-[(2-nitrobenzylsulfanyl]-1H-pyrrole. Molecular modeling revealed two locations in the enzyme H binding site: the catalytic primary one accommodating shorter and longer derivatives and the secondary one, where shorter derivatives can occupy. Derivative 9, displaying the highest inhibition and bearing a p-nitroarylimino moiety, and derivative 4, lacking this moiety, were studied kinetically. Derivative 9 binds (K(i(9)) = 71 ± 4 μM) at the primary site competitively vs CDNB. Derivative 4 binds (K(i(4)) = 135 ± 27 μM) at the primary and secondary sites, allowing the binding of a second molecule (4 or CDNB) leading to formation of unreactive and reactive complexes, respectively. The arylmethylsulfonylpyrrole core structure is a new pharmacophore for hGSTA1-1, whereas its derivative 9 may serve as a lead structure.
authors: Laboratory of Enzyme Technology, Department of Agricultural Biotechnology, Agricultural University of Athens , 75 Iera Odos Street, GR-118 55 Athens, Greece.
authors: Georgia E
authors: GE
authors: Koutsoumpli
authors: Virginia D
authors: VD
authors: Dimaki
authors: Trias N
authors: TN
authors: Thireou
authors: Elias E
authors: EE
authors: Eliopoulos
authors: Nikolaos E
authors: NE
authors: Labrou
authors: George I
authors: GI
authors: Varvounis
authors: Yannis D
authors: YD
authors: Clonis
mesh_terms: D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D057075:Enzyme Assays; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D007097:Imines / Q000138:chemical synthesis* / Q000737:chemistry; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000737:chemistry; D007700:Kinetics; D008958:Models, Molecular; D011485:Protein Binding; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D000814:Aniline Compounds; D007097:Imines; D007527:Isoenzymes; D011758:Pyrroles; D011994:Recombinant Proteins; D013450:Sulfones; D005982:Glutathione Transferase; C119995:glutathione S-transferase alpha