核苷类原生动物化合物的合成与活性,Bioorganic & Medicinal Chemistry

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核苷类原生动物化合物的合成与活性
Bioorganic & Medicinal Chemistry ( IF 3.3 ) Pub Date : 2017-02-17 05:42:43
Huu-Anh Tran, Zhaoyan Zheng, Xianghui Wen, Srinivasan Manivannan, Arnaud Pastor, Marcel Kaiser, Reto Brun, Floyd F. Snyder, Thomas G. Back

寄生虫的原生动物利用挽救途径合成嘌呤并产生必需的活性核苷酸，而哺乳动物则能够从头进行生物合成。这种差异为设计潜在的新抗原生动物化合物提供了机会。基于以下假设制备了一系列47个腺苷类似物，它们在2、6和5'位置进行了修饰，这是基于这样的假设，即此类化合物可作为原生动物核苷挽救酶的底物，而在哺乳动物细胞中仍然是难降解的。核苷经设计可在被寄生虫裂解为相应的嘌呤碱基后产生有毒代谢物。制备了具有相似目的的三种7-脱氮鸟苷衍生物。所有这些化合物均经过体外抗T. brucei（非洲昏睡病），T。cruzi（恰加斯氏病），L。donovani（利什曼病）和恶性疟原虫（疟疾）。为了确定抗原生动物核苷的治疗选择性指数（SI），还测定了它们对大鼠成肌细胞系的细胞毒性。一种腺苷衍生物被证明对恶性疟原虫（IC₅₀ = 110 nM，SI = 1010，而改良的鸟苷显示出对多诺氏乳杆菌（IC ₅₀ = 60 nM，SI = 2720）和布鲁氏梭菌（IC ₅₀ = 130 nM，SI = 1250）的有效活性，以及对克氏锥虫有中等活性（IC ₅₀ = 3.4 µM，SI = 48）。这些结果为基于核苷的抗原生动物策略以及进一步优化和验证的潜在先导化合物提供了概念验证。

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Synthesis and Activity of Nucleoside-Based Antiprotozoan Compounds

Parasitic protozoa employ a salvage pathway to synthesize purines and generate essential active nucleotides, whereas mammals are capable of their de novo biosynthesis. This difference provides opportunity for the design of potential new antiprotozoan compounds. A series of 47 adenosine analogues was prepared with modifications at the 2-, 6- and 5’-positions, based on the hypothesis that such compounds would serve as substrates for protozoan nucleoside salvage enzymes, while remaining refractory in mammalian cells. The nucleosides were designed to produce toxic metabolites upon cleavage to the corresponding purine base by the parasite. Three 7-deazaguanosine derivatives were prepared with similar objectives. All of these compounds were tested in vitro against T. brucei (African sleeping sickness), T. cruzi (Chagas’ disease), L. donovani (leishmaniasis) and P. falciparum (malaria). In order to determine the therapeutic selectivity indices (SI) of the antiprotozoan nucleosides, their cytotoxicities toward a rat myoblast cell line were also determined. One adenosine derivative proved highly effective against P. falciparum (IC₅₀ = 110 nM and SI = 1010, while a modified guanosine displayed potent activities against L. donovani (IC₅₀ = 60 nM, SI = 2720) and T. brucei (IC₅₀ = 130 nM, SI = 1250), as well as moderate activity against T. cruzi (IC₅₀ = 3.4 µM, SI = 48). These results provide proof of concept for the nucleoside-based antiprotozoan strategy, as well as potential lead compounds for further optimization and validation.

更新日期：2017-02-17

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