Design, synthesis, and binding studies of bidentate Zn-chelating peptidic inhibitors of glyoxalase-I.
The known affinity of ethyl acetoacetate (ACC) toward divalent zinc prompted us to attempt its employment as a chelating moiety in the design of glyoxalase-I inhibitors. A practical synthetic route was developed to incorporate this pharmacophore into the side chain of glutamic acid, with flexibility to allow incorporation of additional functionality at the end-stage of the synthesis. Herein, the details of this synthetic approach as well as the evaluation of the resultant beta-keto ester compounds are reported.
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Swati S
SS
Center for Drug Design, Academic Health Center, and Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA.
Vince
Robert
R
D001665:Binding Sites; D002614:Chelating Agents / Q000737:chemistry / Q000494:pharmacology*; D002626:Chemistry, Pharmaceutical / Q000379:methods; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D018698:Glutamic Acid / Q000737:chemistry; D006860:Hydrogen Bonding; D007700:Kinetics; D007791:Lactoylglutathione Lyase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D008024:Ligands; D008956:Models, Chemical; D010100:Oxygen / Q000737:chemistry; D010455:Peptides / Q000737:chemistry; D015032:Zinc / Q000737:chemistry*
D002614:Chelating Agents; D004791:Enzyme Inhibitors; D008024:Ligands; D010455:Peptides; D018698:Glutamic Acid; D007791:Lactoylglutathione Lyase; D015032:Zinc; D010100:Oxygen