Trypanothione synthesis

Enzymes unique to the parasite and not found in humans (e.g., dihydropteroate synthesis enzymes, trypanothione reductase)... 

Reduction of trypanothione levels in the cells may be achieved in two ways (a) by inhibition of trypanothione peroxidase/reductase activity, or (b) by interference with the polyamine biosynthesis. Interference with the polyamine synthesis will not only lead to a decreased turnover of various polyamines, but will also bring down trypanothione levels in cells, thereby, exposing the parasites to the toxic effects of peroxides and free radicals generated by the host. 

Polyamine metabolism by parasites differs in several significant ways from the mammalian host these include, but are not limited to, enzyme half-life, turnover, substrate specificity, types and quantities of polyamines produced. The production of the novel bis glutathionyl spermidine adduct by trypanosomatids, its role as an antioxidant and the protein structure of trypanothione reductase is discussed with respect to the more conventional glutathione reductase system. The role of S-adenosylmethionine and decarboxylated S-adenosylmethionine as critical precursors in the biosynthesis of the higher polyamines is explored with respect to differences in the function and control of the pathway by various parasites. Polyamine biosynthesis in parasites is sufficiently different from that of the host to afford multiple opportunities for drug development, these may be aimed directly at circumventing polyamine biosynthesis or at inhibiting precursors necessary for polyamine synthesis. 

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. 

During the past decade the development of novel protection groups for the directed protection of primary and secondary amines led to a large improvement of the linkers and resins to serve the different needs. The first solid phase syntheses of polyamines were reported by Sergheraert and coworkers [156]. The synthesis of reduced trypanothione disulfide (45) and its oxidized form (46) involved the selective protection of the primary amines of spermidine with a ferf-butyldiphenylsilyl (TBDPS)... 

Scheme 10 Synthesis of oxiized trypanothione (46). Either the di-Boc- or the Boc-Fmoc-spermidine is coupled to the resin 111. After deprotection, the primary amines are further derivatized [162,163,215]. Reagents and conditions a Boc-HN-(CH2)30Ts or 3-bromopropylphthalimide, Na2C03, KI, n-BuOH b Pd/C, H2, EtOH, AcOH c O-(p-nitrophenyl)-0 -(methoxycarbonyl)benzylcarbonate, NEt3, DMF, 97% d aq. NaOH, dioxane in the case of R = Pht N2H4 H2O, EtOH then Fmoc-succinimide e DIG, HOBt, DMAP, aminomethyl resin, DMF or CH2CI2 / deprotection, Fmoc-AS-peptide coupling g TFA/TFMSA/ethanedithiol/PhSMe 12/MeOH [162]...

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