Allopurinol ribonucleoside as an antileishmanial agent. Biological effects, metabolism, and enzymatic phosphorylation.

Allopurinol ribonucleoside [4-hydroxy-1-P-D-ribofuranosylpyrazolo(3,4,-d)pyrimidine] was shown to be more effective than allopurinol in inhibiting the growth of Leishmania promastigotes in vitro. Both allopurinol and its ribonucleoside were equally effective in preventing the transformation of the intracellular form (amastigote) of Leishmania donovani to the extracellular form (promastigote). Promastigotes of 15: donouani, Leishmania braziliensis, and Leishmania mexicana readily converted [6“C]allopurinol ribonucleoside to its 5’-monophosphate derivative. This nucleotide was subsequently aminated and phosphorylated to the 4-aminopyrazolo(3,4-d)pyrimidine analogues of AMP, ADP, and ATP and incorporated into RNA. The marked stability of the ribosyl linkage of allopurinol ribonucleoside was demonstrated with [ribose-U-‘4C]allopurinol ribonucleoside incubated with L. donovani promastigotes. Cell-free extracts of these promastigotes incubated with allopurinol ribonucleoside and ATP failed to phosphorylate allopurinol ribonucleoside. However, in the presence of a variety of monophosphate esters, including p-nitrophenylphosphate, allopurinol ribonucleotide was readily formed from allopurinol ribonucleoside, indicating the involvement of a nucleoside phosphotransferase rather than a nucleoside kinase. These unusual metabolic transformations of allopurinol ribonucleoside reveal large differences between the host and parasite which suggest a potential for chemotherapeutic exploitation.