title: Novel class of bivalent glutathione S-transferase inhibitors.
abstract: Exploiting the principle of bivalent binding, we have designed symmetrical, bifunctional inhibitors to simultaneously occupy both active sites of cytosolic glutathione S-transferase, with enhanced specificity for the P1-1 isoform. We have prepared two series of compounds that differ in their binding domains-the first is a series of bis-glutathione conjugates, and the second is a series of compounds each possessing two equivalents of Uniblue A, an analogue of Cibacron Blue. For each series, a monofunctional reference compound was also prepared to determine the relative advantage of the bivalent inhibitors. Within each series, the most potent inhibitors exhibited IC(50) values 2 orders of magnitude lower than the relevant reference compounds. Moreover, within the bis-glutathionyl series, a 10-fold increase in selectivity was achieved for GST P1-1 over the A1-1 isoform. Isothermal titration calorimetry with a representative bis-glutathione conjugate and a monofunctional reference compound indicates that the bivalent inhibitor exhibits the expected increase in intrinsic affinity and decrease in stoichiometry relative to the monofunctional compound, supporting the overall design strategy.
authors.affiliation: Department of Medicinal Chemistry, Box 357610, University of Washington, Seattle, Washington 98195-7610, USA.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Lyon
authors.forename: John J
authors.initials: JJ
authors.lastname: Hill
authors.forename: William M
authors.initials: WM
authors.lastname: Atkins
mesh_terms: D000818:Animals; D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000145:classification / Q000378:metabolism*; D005978:Glutathione / Q000737:chemistry* / Q000378:metabolism; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D011487:Protein Conformation; D014227:Triazines / Q000737:chemistry / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D007527:Isoenzymes; D014227:Triazines; C012842:Cibacron Blue F 3GA; D005982:Glutathione Transferase; D005978:Glutathione