Potential Inhibitors of Phospho enolpyruvate (pep) Carboxylase: Phosphonic Acid Substrate Analogues Derived from Stobbe-Type Condensations of Ethyl 3-(Diethoxyphosphinoyl)propanoate

Phosphonic acid analogues of 2-(dihydroxyphosphinoyloxy)propenoic acid (pep), the substrate of pep carboxylase, were prepared and tested as inhibitors of the enzyme. The required triacids were obtained by mild hydrolysis of the partial esters prepared by Stobbe-like condensation of aryl and alkyl carbonyl compounds with ethyl 3-(diethoxyphosphinoyl)propanoate. Condensations with aldehydes gave predominantly (Z)-propenoates while reactions with ketones gave mixtures of (E)- and (Z)-isomers and also, in some cases, products with the double bond rearranged to the β-position. Although compounds tested were inhibitory, none was as effective as previously reported phosphate pep analogues. Results indicate that the presence of a methyl group cis to the carboxylic acid group enhances inhibitory activity but that trans alkyl groups decrease inhibitor effectiveness.