Analogs of ornithine as inhibitors of ornithine decarboxylase. New deductions concerning the topography of the enzyme's active site

Abstract

Fourteen structural analogs of ornithine were synthesized and evaluated as inhibitors of preparations of the enzyme L-ornithine carboxylyase (ODC) (EC 4.1.1.17) obtained from rat liver, rat hepatoma cells in culture, or bull prostate. The synthesis of these compounds was achieved either via a Bucherer type reaction or via alkylation of carbanions derived from ethyl acetamidocyanoacetate, methyl isocyanoacetate, benzyl .alpha.-isocyanopropionate, methylbenzaldimine alanate and the azlactone derivative of ornithuric acid. (+)-.alpha.-Methylornithine, which was assigned the L configuration on the basis of rotational criteria, was found to be the most potent reversible inhibitor of ODC among the synthesized compounds. From the degree of inhibition of ODC activity in the presence of the various ornithine analogs, it was possible to delineate some of the structural features of the substrate L-ornithine which are required for binding to the mammalian ODC active site.