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-1 inhibitors. A practical synthetic route was developed to incorporate this pharmacophore into the side chain of glutarnic acid, with flexibility to allow incorporation of additional functionality at the end-stage of the syllthesis. Herein, the details of this synthetic approach as well as the evaluation of the resultant P-keto ester compounds are reported. (c) 2007 Elsevier Ltd. All rights reserved.