Specific inhibitory effect of 3-deazaneplanocin A against several Leishmania mexicana and L. braziliensis strains.

Abstract

The growth inhibitory effect of 3-deazaneplanocin A (c3NpcA) was tested against some pathogenic members of the family of American Trypanosomatidae. Under our culture conditions, c3NpcA displayed a strongly and uniformly leishmanistatic effect on all 23 American Leishmania (L. mexicana and L. brasiliensis) strains in the study (mean dose producing 50% inhibition compared with control parasite growth [ID50] = 96 ng/ml, 0.32 microM), but showed no inhibition against the several T. cruzi and T. rangeli strains tested with concentrations up to 10,000 ng/ml. This compound also induced a substantial expansion of the intracellular pools of both S-adenosylhomocysteine (AdoHcy) and S-adenosylmethionine (AdoMet), as well as a significant diminution of the AdoMet:AdoHcy ratio. Strong AdoHcy hydrolase activity was detected in American Leishmania promastigotes. At at a dose of 200 ng/ml, c3NpcA inhibited S-adenosyl-L-3H-methylmethionine and 3-thymidine incorporation by promastigotes after four days incubation in the presence of the drug. At a dose of 100 ng/ml, c3NpcA eliminated approximately 56% of the L. mexicana and L. brasiliensis from infected human macrophages, compared with simultaneously cultivated controls. Two schedules of 10 consecutive intraperitoneal injections of c3NpcA, with doses ranging from 0.5 to 1.5 mg/kg/day, significantly reduced development of cutaneous leishmanial infection produced in inbred BALB/c mice by L. b. guyanensis inoculation, although a few parasites remained at the inoculation site.