Polyamine biosynthesis inhibitors

Biosynthesis of polyamines is essential for growth and multiplication of T. brucei, hence discovery of drug candidates that inhibit enzymes in the polyamine biosynthesis pathway represent an attractive approach to development of trypanocides. The consequences of gene knockout of ornithine decarboxylase (ODC), the target of eflornithine (3), have been further characterized and suggest that new inhibitors of this enzyme may be particularly effective [18]. 

A third enzyme in the polyamine biosynthesis pathway, trypanothione synthetase-amidase (TRYS), has been shown to be essential by both genetic and chemical methods [24]. Specifically, the indazole analog 24 has been identified in a TRYS screen (IC50 = 140 nM) and shown to inhibit growth of wild-type (IC50 = 5.1 pM) and TRYS-dKO (IC50 = 0.46 mM) T. brucei parasites in culture [25]. 

One of the most compelling targets in the polyamine biosynthesis pathway has been S-adenosylmethionine decarboxylase (SAM-DC). This target was chemically validated with the discovery of trypanocidal activity of MDL-73811 nearly two decades ago. Work to understand the unique kinetics for inhibition of this enzyme in T. brucei has shown that a catalytically 

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Byers, T. L., Bush, T. L., McCann, P. P. and Bitonti, A. J. (1991) Antitrypanosomal effects of polyamine biosynthesis inhibitors correlate with increases in Trypanosoma brucei brucei S-adenosyl-L-methionine. Biochem. J. 274 527 533. 

Ornithine decarboxylase (ODC) is the first enzyme in the polyamine biosynthesis pathway. Polyamines play essential roles in cell proliferation and differentiation and participate in macromolecular synthesis. Inhibitors of ODC block aspects of tumor promotion and induce cellular differentiation in several animal carcinogenesis models. Thus induction of ODC has been implicated as being important to carcinogenesis, and ODC activity is an intermediate biomarker of cell proliferation in studies... 

Depletion of polyamines by the bis(benzyl)polyamines and ODC inhibitors prevents transformation of trophozoites to schizonts (25, 27-29). Similarly, inhibition of growth with bis(benzyl)polyamines has been observed for Leishmania (30). These observations strongly suggest that enzyme product interactions have a role in regulation of polyamine biosynthesis in Plasmodium spp. and Leishmania spp. However, L. donovani ODC, unlike the mammalian enzyme, is not negatively regulated by polyamines (16). 

SAMDC) inhibitor. SAMDC is another rate-limiting enzyme of polyamine biosynthesis. 

S. adenosylmenthionine decarboxylase (AdometDC) are two enzymes of polyamine biosynthesis in cells induces metagenesis in cells which leads cancer development, ODC inhibitor DFMO induces polyamine depletion result cytostatic growth inhibitor [5],... 

Cheetham, B. F., and Bellett, A. J. D., 1982, A biochemical investigation of the adenovirus-induced G1 to S phase progression Thymidine kinase, ornithine de-carbozylase and inhibitors of polyamine biosynthesis, J, Cell. Physiol. 110 114. 

SSAT induction is observed in response to treatment with NSAIDs, and this induction contributes to the antiproliferative activity of NSAIDs in regard to the development of colorectal carcinoma (Babbar et al. 2003, 2006a). Recently, a phase IB clinical trial examined the chemopreventive potential of combining treaunent with a specific NSAID (sulindac) with an inhibitor of polyamine biosynthesis (difluoro-methylomithine) (Meyskens et al. 2(X)8). Patients in this study who received the combination therapy demonstrated dramatic reductions in the occurrence of colon... 

Bacteria and animals use ornithine decarboxylase in polyamine biosynthesis. However, the transport system for polyamines in bacteria through transporters is different from that of animals through endocytosis (Uemura et al. 2010). Some bacteria and most animals use ornithine decarboxylase for polyamine biosynthesis. However, the polyamine transport systems in bacteria are different from those of animals, which employ endocytosis (Uemura et al. 2010). Therefore, in view of the potential adverse effects that could result from the inhibition of polyamine biosynthesis in human, using an inhibitor of polyamine transport as a drug for prevention and control of pathogenic bacteria is a more attractive chemotherapeutic target than polyamine biosynthesis. 

S.2.3.3 Treatment of Trypanosomiasis The difluoromethylornithine (DFMO), eflomithine is a mechanism-based inhibitor of ornithine decarboxylase— a pyridoxal-dependent key enzyme of the polyamine s biosynthesis from ornithine. Fluorine atoms are essential for the inhibition process (cf. Chapter 7). Eflornithine was first clinically developed for cancer, but its development has been abandoned for this indication. The activity of eflornithine on trypanosomes was then discovered. Now, despite its very low bioavailability, eflornithine is the best therapy for sleeeping sickness (trypanosomiasis)—in particular, at the cerebral stage—due to Trypanosoma brucei gambiense parasite. Eflornithine is registered with orphan drug status and is distributed by the WHO. 

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