Polyamines synthesis, inhibitors

Certain noncarcinogenic PAH and environmental contaminants Polyamine synthesis inhibitors (DMFO, retinoids)... 

ACS activity may be reversibly regulated by various substances associated with the methionine-recycling pathway, SAM metabolism, and polyamine synthesis, and by natural and chemical analogues of SAM or inhibitors of PLP-dependent enzymes. 

Ethambutol is a synthetic agent and not related to any of the other tuberculostatics. Its mechanism of action is not well understood but in actively dividing mycobacteria it appears to be an inhibitor of mycobacterial RNA synthesis. It also has effects on bacterial phosphate metabolism and on polyamine synthesis. It is an bacteriostatic agent and its main function in combination therapy is to delay the occurrence of resistance, mainly against isoniazid and rifampicin. It is well absorbed after oral administration. It is widely distributed, except to the CNS. Protein binding is about 20-30%. It is mainly excreted unchanged in the bile and urine with an elimination half-life of 3 h. Ethambutol is concentrated in erythrocytes and thus provides a depot for continuous release. 

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... 

Further modifications using the same strain of ODC S. cerevisiae reconstituted a bacterial/plant polyamine synthesis pathway in yeast [41], The ODC strain was transformed with plasmids encoding arginine decarboxylase and ag-matine ureohydrolase, which conferred polyamine-independent growth on the recombinant microbe. A similar construction could be used to screen for inhibitors of the homologous enzymes from Apicomplexan protozoa, which synthesize poly amines through this pathway [42]. 

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... 

Bagni, N., Torrigiani, P, and Barbieri, P, Effect of various inhibitors of polyamine synthesis on the growth of Helianthus tuberosus, Med. Biol., 59, 403-409, 1981. 

The IGF-I-independent actions of GH are exerted primarily in hepatocytes. GH administration is followed by an early increase in the synthesis of 8 to 10 proteins, among which are IGF-I, a2-macroglobulin, and the serine protease inhibitors Spi 2.1 and Spi 2.3. Expression of the gene for ornithine decarboxylase, an enzyme active in polyamine synthesis (and, therefore, in the regulation of cell proliferation), is also significantly increased by GH. 

The inhibition of cellular protein synthesis is inevitably followed by the decline of the functions of unstable proteins with possible widespread effects on the cell. It has been observed that the activity of enzymes controlling polyamine synthesis (McCormick and Newton, 1975) and of RNA polymerases I and II, measured in isolated nuclei, declined after infection (Preston and Newton, 1976). However, the rate of decline was faster than occurred after adding cycloheximide to uninfected cells, suggesting that the polymerases may have been inactivated by interaction with some virus-specific protein. Lowe (1978) could detect no changes in the activities of purified RNA polymerases in infected cells but extraction of the enzymes may possibly restore their activity by dissociation of an inhibitor. It would be interesting to have a direct comparison between the polymerase activities measured in intact nuclei and after purification. 

Nagarajan, M. Xiao, X. Antony, S. Kohlha-gen, G. Pommier, Y. Cushman, M. Design, synthesis, and biological evaluation of indeno-isoquinoline topoisomerase I inhibitors featuring polyamine side chains on the lactam nitrogen./. Med. Chem. 2003, 46, 5712-5724. 

Inhibitors of DNA synthesis and cell replication are TGF-jl and HPI (= hepatic proliferation inhibitor). Their function is to block the growth-promoting factors once the nominal size of the liver has been reached. The regeneration course is, however, also linked to a complex network of biochemical processes, including the polyamines (putrescine, spermidine and spermine) as well as the precursors of nucleic acids (orotate, thymidine and uridine). (17, 33, 47-49, 55, 56)... 

Aliphatic amines and polyamines are bases nearly as weak as ammonia. Alkyl amine hydrochlorides are used rarely now in view of the recognised toxicity. They are known in free or salt form as corrosion inhibitors, flotation collectors and adhesion promoters for asphalt coatings. Acylated polyamines are of interest for the amphoteric biocide synthesis. 

Metcalf et al. (23) reported the synthesis of efiornithine (difluoromethyl ornithine [DFMO]) in 1978. Their interest arose from the desire to prepare ornithine decarboxylase (ODC) inhibitors as tools for studying the role of polyamines as regulators of growth processes. Ornithine decarboxylase catalyzes the conversion of ornithine to putrescine (1,4-diaminobutane), which in turn leads to the formation of the polyamines, spermine, and spermidine. It was not until 1980 that Bacchi et al. (24) demonstrated the potential of DFMO in the treatment of trypanosomiasis. 

African sleeping sickness, another widespread epidemic, is caused by Trypanosoma brucei, which is transmitted by flies. Ornithine decarboxylase (ODC), a key enzyme in the pathway for the synthesis of polyamines, is a target enzyme for drug development. Alpha-diflnoromethyl ornithine, an irreversible inhibitor of ODC, has been developed for the treatment of sleeping sickness (93). 

A common inhibitor of the latter enzyme is the polyamine alkaloid kukoamine A (10). The synthesis of trypanothione and kukoamine A and their analogs was recently performed on solid support, as described in Sect. 3.2. 

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