Spermidine synthase inhibitors

Ornithine decarboxylase is specifically inhibited by the enzyme-activated inhibitor a-difluoromethyl-ornithine, which can cure human infection with Trypanosoma brucei (African sleeping sickness) by interfering with polyamine synthesis.243-2443 In combination with inhibitors of spermidine synthase or S-adenosylmethionine decarboxylase,245 it can reduce polyamine levels and growth rates of cells. Another powerful inhibitor that acts on both ornithine and adenosylmethionine decarboxylases is the hydroxy-lamine derivative l-aminooxy-3-aminopropane 246... 

Dufe, V. T., Qiu, W., Muller, I. B., Hui, R., Walter, R. D., and Al-Karadaghi, S. (2007). Crystal structure of Plasmodium falciparum spermidine synthase in complex with the substrate decarboxylated S-adenosylmethionine and the potent inhibitors 4MCHA and Ado-DATO. ]. Mol. Biol. 373,167-177. 

Fig. 2. Biogenetic links between A primary metabolism and B the alkaloid-specific pathway. CAP, N-carbamoylputrescine GABA, 4-aminobutyric acid. Inhibitors DFMA, a-difluorome-thylarginine, HEH, /1-hydroxyethylhydrazine. Enzymes 1, arginine decarboxylase 2, agmatine iminohydrolase 3, JV-carbamoylputrescine amidohydrolase 4, diamine oxidase 5, pyrroline dehydrogenase (NAD+-dependent) 6, spermidine synthase 7, a putrescine-producing poly-amine oxidase (H H-insensitive) 8, homospermidine synthase 9, an HEH-sensitive polyamine oxidase...

A Wadsworth-Emmons reaction on an adenosine 5 -aldehyde derivative was a key step in the synthesis of adenosylspermidine (214), an inhibitor of spermidine synthase. ... 

The aminopropylation of spermidine into spermine by spermine synthase (SPM synthase) is favored by a higher basicity (ease of protonation) of the nitrogens N-1 and N-4, but also by a lower basicity of N-8 of the butylamino terminal group (more difficult protonation). This last factor enhances the affinity of the substrate for the enzyme. Fluorospermidines could then appear as potential inhibitors of SPM synthase. Indeed, the presence of fluorine atoms in P of an amino group lowers the basicity of the amine the pK value of N-4 is lowered by 2.70 units for... 

No specific inhibitor for spermine synthase has been described, but 5 -meth-ylthioadenosine (Hibasami et al, 1980b), 5 -methylthiotubercidin (Pajula and Raina, 1979), and aurintricarboxylic acid (Hibasami e/a/., 1982) inhibit both spermidine and spermine synthases. 

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