Laboratory and clinical investigations of pyrazolopyrmidines and other purine base and nucleoside analogues have shown that compounds of this general chemical group possess significant chemotherapeutic activities against the pathogenic hemoflagellates. One of these compounds, allopurinol ribonucleoside, which was developed in this laboratory in collaboration with other scientists, has entered clinical trials in three foreign countries. The accumulated experimental data recently has directed attention to analogues of inosine, particularly those in which the ribose is not readily cleaved from the base by mammalian cells. Among these are certain C- nucleoside analogues, compounds in which the ribose is linked to the base by a carbon-carbon bond rather than the usual carbon- nitrogen bond. A prototype, 9-deazainosine, was chosen for further study because of its broad antiprotozoan activity and apparent lack of toxicity to certain mammalian cells. A more recently described antiprotozoan inosine analogue, 3'- deoxyinosine, is modified in the ribose moiety yet retains substantial activity against certain species of leishmania. this proposal is to study the metabolism of these two analogues of inosine in detail in order to generalize on modifications of the purine ring structure and ribose moiety which will procide the maximum antiprotozoan efficacy with a minimum of mammalian cell toxicity. To this end 9-deazainosine and 3'-deoxyinosine will be studied in Leishmania donovani and Trypanosoma cruzi. These studies will be done in vitro using tissue culture methods in order to utilize the intracellular pathogenic forms of these parasites. An investigation of the therapeutic efficacy of 9-deazainosine in animal models of T. cruzi infection also will be undertaken. Of special importance with respect to structural modifications as they relate to chemotherapy will be an investigation into the enzymatic activation of inosine analogues and correlation of their biological activities with their solution conformations.
| Gallerano, R H; Marr, J J; Sosa, R R (1990) Therapeutic efficacy of allopurinol in patients with chronic Chagas' disease. Am J Trop Med Hyg 43:159-66 |
