Effects of Certain 5'-Substituted Adenosines on Polyarnine Synthesis: Selective Inhibitors of Spermine Synthase

A number of nucleosides related to S-adenosylmethionine were tested for their inhibitory action on three enzymes involved in the biosynthesis of polyamines. The particular objective of the experiments was to determine whether any of the compounds could be used as selective inhibitors of the synthesis of spermine by spermine synthase. None of the nucleosides examined were potent inhibitors of S-adenosylmethionine decarboxylase. 5^'-[(3-Aminopropyl)amino]-5^'-deoxyadenosine dihydrochloride was quite a strong inhibitor of spermidine synthase (/₅₀ of 7 μM) but was more than an order of magnitude less active than S-adenosyl-1,8-diamino-3-thiooctane, which is a mechanism-based inhibitor of this enzyme. 5'-[(3-Aminopropyl)amino]-5'-deoxyadenosine also inhibited spermine synthase with an I₅₀ of 17 μM, but more selective inhibition of spermine synthase was produced by 9-[6(RS),8-diamino-5,6,7,8-tetradeoxy-β-D-ribo-octofuranosyl]-9H-purin-6-amine (I₅₀ of 12 μM) and by dimethyl(5'-adenosyl)sulfonium perchlorate (I₅₀ of 8 μM) since these compounds were much less active against spermidine synthase. Both 9-[6(RS),8-diamino-5,6,7,8-tetradeoxy-β-D-ribo-octofuranosyl]-9H-purin-6-amine and dimethyl(5'-adenosyl)sulfonium perchlorate were able to reduce the synthesis of spermine in SV-3T3 cells, but there was a compensatory increase in the concentration of spermidine, and there was no effect on cell growth. These results and those from experiments in which these spermine synthesis inhibitors were combined with inhibitors of spermidine synthase and ornithine decarboxylase indicated that the cells compensated for the inhibition of the aminopropyltransferases by increasing the production of decarboxylated S-adenosylmethionine and putrescine. It appears therefore that it is necessary to limit the synthesis of decarboxylated S-adenosylmethionine in order to fully exploit the potential of these inhibitors to block polyamine synthesis.