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

P Bey, C Danzin, V Van Dorsselaer… - Journal of Medicinal …, 1978 - ACS Publications
P Bey, C Danzin, V Van Dorsselaer, P Mamont, M Jung, C Tardif
Journal of Medicinal Chemistry, 1978ACS Publications
Fourteen structural analogues of ornithine were synthesized and evaluated as inhibitors of
preparations of the enzyme L-ornithine carboxylyase (ODC)(EC 4.1. 1.17) obtainedfrom 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-isocyanopropionate,
methylbenzaldimine alanate, and the azlactone derivative ofornithuric acid.(+)-a …
Fourteen structural analogues of ornithine were synthesized and evaluated as inhibitors of preparations of the enzyme L-ornithine carboxylyase (ODC)(EC 4.1. 1.17) obtainedfrom 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-isocyanopropionate, methylbenzaldimine alanate, and the azlactone derivative ofornithuric acid.(+)-a-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 ofODC activity inthe presence of the various ornithine analogues, it has been possible to delineate some of the structural features of the substrate L-ornithine which are required for binding to the mammalianODC active site.
Numerous investigations clearly indicate that the polyamines, spermidine and spermine, and their diamine precursor, putrescine, have essential functions in cellular mechanisms, particularly those involved in cell division. 1 A possible way of elucidating the biological roles of these bioamines is to selectively impair their biosynthesis. 2 In eukaryotic organisms the conversion of ornithine to putrescine catalyzed by ornithine decarboxylase (ODC)(l-ornithine carboxylyase EC 4.1. 1.17) is believed to be the obligatory and rate-limiting step for their biosynthesis, 3 a concept that has ledto the search for specific inhibitors of this enzyme. Thus far, the substrate analogues 2-hydrazino-5-aminopentanoic acid, 4 DL-a-methylornithine, 5 DL-2-hydrazino-2-methyl-5-aminopentanoic acid, 6 N-(5'-phosphopyridoxyl) ornithine, 7 and DL-(E)-2, 5-diamino-3-pentenoic acid8 have been found to be potent reversible inhibitors of ODC.
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