Diane Susan Braccolino

EPSP Synthase: The Design and Synthesis of Bisubstrate Inhibitors Incorporating Novel 3-Phosphate Mimics

Abstract Novel aromatic bisubstrate inhibitors of the enzyme EPSP (5-enolpyruvoylshikimate-3-phosphate) synthase (EC 2.5.1.19) have been designed and synthesized as structural analogs of the single, catalytic intermediate 1 utilized by the enzyme. These aromatic inhibitors incorporate novel α-hydroxyphosphonates, malonate ethers and α-hydroxymalonates as replacements for the hydrolytically labile 3-phosphate group. These 3-phosphate mimics were much preferred to the corresponding methylene and vinylic phosphonates, malonates and phosphonomethyl ethers.

EPSP synthase inhibitor design IV. New aromatic substrate analogs and symmetrical inhibitors containing novel 3-phosphate mimics.

Abstract New 4-deoxy aromatic analogs of S3P and EPSP have been synthesized as potential substrate-based inhibitors of EPSPS to evaluate various 3-phosphate replacements in combination with the aromatic ring system. These studies identified 3-malonate ethers and α-hydroxymethylphosphonates as suitable 3-phosphate mimics in this series and led to the discovery of two unexpectedly potent symmetrical aromatic inhibitors 6 and 7 .

EPSP synthase inhibitor design II. The importance of the 3-phosphate group for ligand binding at the shikimate-3-phosphate site & the identification of 3-malonate ethers as novel 3-phosphate mimics.

Abstract Studies using alternate substrates, inhibitor product mimics and new derivatives of 4,5-dideoxy-shikimate-3-phosphate (ddS3P) are reported which indicate that the 3-phosphate group contributes significantly to substrate and inhibitor recognition at the shikimate 3-phosphate (S3P) site and that 3-malonate ethers will function as suitable 3-phosphate replacements for substrate and inhibitor binding to the S3P site of this enzyme.