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A well-defined series of 5'-([(Z)-4-amino-2-butenyl]methylamino)-5'-deoxyadenosine analogues was designed and synthesized in order to further ascertain the optimal structural requirements for S-adenosylmethionine decarboxylase inhibition and potentially to augment and perhaps separate their antiproliferative and antitrypanosomal activities. Most structural modifications had a deleterious affect on both the antitrypanosomal and antineoplastic activity of 5'-([(Z)-4-amino-2-butenyl]methylamino)-5'-deoxyadenosine. However, di-O-acetylation of the parent compound produced a potential prodrug that caused markedly pronounced inhibition of trypanosomal and neoplastic cell growth and viability. Moreover, the acetylated derivative of 5'-([(Z)-4-amino-2-butenyl]methylamino)-5'-deoxyadenosine did inhibit HIV-1 growth and infectivity, whereas the parent compound did not.

The (+)-enantiomer of 7-deaza-5'-noraristeromycin (4) has been found to show IC50 values ranging from 0.16 to 5.3 microM against four strains of African trypanosomes, one Trypanosoma brucei brucei isolate, and several clinical isolates of Trypanosoma brucei rhodesiense (agent of east African sleeping sickness), including a multidrug resistant clone of one isolate. While this compound was originally designed to inhibit S-adenosyl-L-homocysteine hydrolase, it has been found to have no effect on this enzyme.

A recent observation that (+)-7-deaza-5'-noraristeromycin (1), as an L-like analogue of aristeromycin, possessed meaningful anti-trypanosomal properties has prompted a search of other 7-deazapurines with similar or improved anti-trypanosomal responses. In that direction a series of pyrazolo[3,4-d]pyrimidines (that is, 8-aza-7-deaza-5'-noraristeromycin derivatives, 2-11) related to 1 have been prepared. These derivatives were evaluated against bloodstream forms of Trypanosoma brucei brucei and Trypanosoma brucei rhodesiense grown in vitro. Of these compounds, the parent L-like derivative 2 was less potent (IC50 40-70 microM) than 1 (IC50 0.165-5.3 microM) whereas the D-like analogue 3 was inactive, which is the same trend observed previously with 7-deaza-5'-noraristeromycin. Interestingly, some moderate activity (IC50 12.2-16.8 microM) was seen in the D-like 4'-methyl derivative 7 while its L-like partner was inactive.

The S-adenosylmethionine (AdoMet) analogue S-(5'-deoxy-5'-adenosyl)-1-aminoxy-4-(methylsulfonio)-2-cycl opentene (AdoMao) was synthesized in two of its four possible diastereomeric forms using a facile chemoenzymatic route. The trans-1R,4R- and trans-1S,4S-diastereomers of AdoMao, as well as the corresponding diastereomers of the unmethylated precursor molecule nor-AdoMao, were then evaluated as inhibitors of S-adenosylmethionine decarboxylase (AdoMet-DC) from both bacterial and human sources. All four of the analogues acted as time-dependent, irreversible inhibitors of AdoMet-DC from Escherichia coli, exhibiting remarkably constant Ki values ranging between 20.6 and 23.7 microM. These analogues also inhibited the human form of AdoMet-DC, although this form of the enzyme was able to discriminate between AdoMao (Ki values of 21.2 microM for the trans-1R,4R form and 19.6 microM for the trans-1S,4S form) and nor AdoMao (Ki values of 95.2 microM for the trans-1R,4R form and 30.9 microM for the trans-1S,4S form). The trans diastereomers of AdoMao and nor-AdoMao were next evaluated for their ability to inhibit trypanosomal growth in vitro against cultured Trypanosoma brucei brucei bloodforms. All four of these analogues were effective growth inhibitors, with IC50 values ranging between 0.9 and 10.1 microM. The two most effective analogues, trans-1S,4S-AdoMao (IC50 0.9 microM) and trans-1S,4S-AdoMao (IC50 3.0 microM) were also effective against two clinical isolates of the pathogenic organism Trypanosoma brucei rhodesiense, KETRI 243 and KETRI 269. The most promising analogue in all respects was trans-1S,4S-AdoMao, which was subsequently found to have minimal effects on cell growth, AdoMet-DC activity, and intracellular polyamine levels in the sensitive human promyelocytic leukemia cell line HL60. Thus, the S-adenosylmethionine analogue trans-1S,4S-AdoMao acts as an effective inhibitor of AdoMet-DC and appears to serve as a parasite-specific trypanocidal agent in vitro.

The triazole nucleoside derivatives 1-(5'-O-sulfamoyl-beta-D-ribofuranosyl) [1,2,4]triazole-3-carboxamide (2), 1-(5'-O-sulfamoyl-beta-D-ribofuranosyl) [1,2,4]triazole-3-thiocarboxamide (3), and 1-(5'-O-sulfamoyl-beta-D-ribofuranosyl)-[1,2,4]triazole-3- carbonitrile (4) were synthesized. Suitably protected triazole nucleosides were converted to their corresponding 5'-sulfamoyl derivatives, which on subsequent deprotection gave the desired compounds in good yields. The structures of compounds 2-4 were confirmed by X-ray crystallographic analysis. All three compounds showed significant antiparasitic activity in vitro, while 2 showed significant activity in vivo against Leishmania donovani and Trypanosoma brucei.