Anti-Parasitic Activity of Nucleoside Analogues against Leishmania tropica and Leishmania donovani.

开发具有选择性毒性的化疗药物的一个有前景的方法是基于寄生虫不同于宿主细胞的结构或功能的某些独特特征的方法。利什曼原虫不能从头合成嘌呤，因此依赖于宿主提供穿孔嘌呤的来源。寄主和寄生虫体内嘌呤回收酶和相互转化途径的这种质的差异，为寄生虫选择性毒性药物的设计提供了一条合理的途径。我们发现了3‘-脱氧肌苷。卡环肌苷、7-脱氮胞苷和3‘-脱氧-3’-氟肌苷对利什曼原虫前鞭毛体有较强的抑制作用，但对哺乳动物细胞的毒性显著降低。将贴壁细胞暴露于杜氏乳杆菌前鞭毛体1d，并用该药处理。用肌苷类似物(3‘-脱氧肌苷、碳环肌苷、7-脱氮胞苷和3’-脱氧-3‘-氟肌苷)对感染杜氏钩端螺旋体的BALB/C小鼠进行治疗。感染杜氏乳杆菌前鞭毛体的小鼠每隔一天给予5种不同剂量的药物治疗。印模后2周取肝脏涂片，测定1000个肝细胞核的寄生虫载量，以LDU表示。在感染杜氏钩端螺旋体的小鼠中，3‘-脱氧肌苷100 mg/kg静脉注射的有效率约为对照组的78%，卡环肌苷100 mg/kg静脉注射的有效率为92%。7-脱氮胞苷和3‘-脱氧-3’-氟肌苷对感染小鼠也有一定的抑制作用。

A promising approach for the development of chemotherapeutic agents possessing selective toxicity is the one based on certain unique features in structure or function of the parasite that differ from those of the host cells. Leishmania are incapable of synthesizing purine de novo and are thus dependent on the host for the source of performaed purine. This qualitative difference in the enzymes of purine salvage and interconversion pathway between host and parasite suggests a rational approach towards the design of agents selectivitgy toxic in the parasite. We found that 3'- deoxyinosine. carbocyclic inosine, 7-deazainosine and 3'-deoxy-3'-fluoroinosine area potent inhibitors of promastigotes of Leishmania but significantly less toxic mammalian cells.In the present experiments, J774.1, a mouse macrophage line, was cultured in RPMI 1640 medium containing lipopolysaccharide. The adherent cells were exposed to promastigotes of L. donovani for 1 day, and treated with the drug. The results indicate that inosine analogues are active against amastigotes of L. donovani in vitro.The BALB/C mice infected with L. donovani were treated with inosine analogues (3'- deoxyinosine, carbocyclic inosine, 7-deazainosine and 3'-deoxy-3'-fluoroinosine) for appraising those therapeutic effect. The mice infected with L. donovani promastigotes were treated with 5 different doses of each drug administered on alternative days. Two weeks after the impression smear of the liver was prepared to determine the parasite load which was expressed as LDU by 1000 hepatic cell nuclei. In the mice infected with L. donovani, 3'-deoxyinosine 100 mg/Kg I.V showed about 78 % effect as compared with control group, and carbocyclic inosine 100 mg/Kg I. V. showed 92 % effect. 7-Deazainosine and 3'-deoxy-3'-fluoroinosine were also effective against the infected mice.