tisopurine and 4-aminopyrazolo(3-4-d)pyrimidine

We investigated the antileishmanial actions of the pyrazolopyrimidines allopurinol (4-hydroxypyrazolo[3,4-d]pyrimidine), thiopurinol (4-thiopyrazolo[3,4-d]pyrimidine), and aminopurinol (4-aminopyrazolo[3,4-d]pyrimidine). These compounds affect several metabolic processes. The first is the inhibition of GMP reductase by the IMP analogues allopurinol ribonucleoside monophosphate and thipurinol ribonucleoside monophosphate which reduces the organism's ability to synthesize ATP from guanine. Second, interconversion of adenine nucleotides to guanine nucleotides, is curtailed by the inhibition of IMP dehydrogenase by these same IMP analogues. Third, the IMP analogues reduce intracellular UTP content. The fourth affect is increased catabolism of RNA and consequent reduction of protein synthesis. This latter effect is due to the adenine nucleotide analogues aminopurinol ribonucleoside mono-, di-, and/or triphosphates, metabolic products of both allopurinol and aminopurinol.

Topics: Adenine; Adenosine Triphosphate; Allopurinol; Animals; GMP Reductase; IMP Dehydrogenase; Leishmania donovani; NADH, NADPH Oxidoreductases; Protein Biosynthesis; Purine Nucleotides; Ribonucleosides; Ribonucleotides; RNA; Thionucleosides; Thionucleotides; Uridine Triphosphate

Strains of Trypanosoma cruzi differ in their susceptibilities to and metabolism of pyrazolopyrimidines. Allopurinol riboside can control but not eliminate infections with a sensitive strain in both tissue culture and mice. Formycin B, which proved to be greater than 10-fold more effective on a weight basis, showed a similar strain specificity but could eliminate an infection with a sensitive strain from tissue culture. However, this drug, unlike allopurinol riboside, was converted to toxic analogues of adenosine mono-, di-, and triphosphate by uninfected tissue culture cells. Thiopurinol and its riboside were effective against all strains unless culture was performed in purine-defined medium. Thus formycin B and allopurinol riboside appear to be good models for the design of antitrypanosomal agents. Suitable modification of the molecule may provide an effective chemotherapeutic agent.

Topics: Adenine; Allopurinol; Animals; Antiprotozoal Agents; Chagas Disease; Drug Resistance; Formycins; Inosine; Mice; Mice, Inbred DBA; Ribonucleosides; Thionucleosides; Trypanosoma cruzi

The pathogenic hemoflagellates of the genera Leishmania and Trypanosoma are major causes of human disease in the tropical and subtropical areas of the world. In general, the agents used to treat diseases caused by these organisms are toxic and not suitable for administration to the millions of people infected. Investigations over the past several years have shown that there are several major differences between man and these protozoans with respect to purine metabolism. The differences appear to offer promise for the development of effective chemotherapeutic compounds. These organisms do not synthesize purines de novo, as does man. They are able to concentrate pyrazolopyrimidines with the cell and metabolize them as purines through the salvage pathways, ultimately incorporating them into nucleic acids. This does not occur in mammals. The pyrazolopyrimidine base allopurinol, which has served as a prototype, is activated by a phosphoribosyltransferase to the ribonucleotide. The ribonucleotide is aminated to the 4-amino-pyrazolopyrimidine ribonucleotide and subsequently phosphorylated to the triphosphate form and incorporated into RNA. The pyrazolopyrimidine ribonucleosides formycin B and allopurinol ribonucleoside are activated through a nucleoside phosphotransferase. The resulting ribonucleotide is aminated and incorporated into RNA as described above. These metabolic peculiarities occur not only in the forms of these parasites which are found in the insect vectors but also in the intracellular forms which are pathogenic in man. The differences in the enzymology and metabolism of purines which exist in the genera Leishmania and Trypanosoma offer excellent opportunities for chemotherapeutic exploitation.

Topics: Adenine; Allopurinol; Animals; Formycins; Host-Parasite Interactions; Leishmania; Ribonucleosides; Thionucleosides; Trypanosoma cruzi