Evaluation of the antiprotozoan properties of 5′-norcarbocyclic pyrimidine nucleosides
Evaluation of the antiprotozoan properties of 5′-norcarbocyclic pyrimidine nucleosides
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DOI：
10.1016/j.bmcl.2017.05.052
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发表时间：
2017-07-15
影响因子：
2.7
通讯作者：
de Koning, Harry P.
中科院分区：
文献类型：
--
作者：
Alzahrani, Khalid J.;Matyugina, Elena S.;de Koning, Harry P.
碳环核苷类似物作为抗感染剂，包括关键的抗病毒剂，具有杰出的历史。毒性最初是一个问题，但这是通过引入5 '-nor变体而减少的。在这里，我们报告的结果，我们的初步筛选的一系列5 '-norcarbocyclic尿苷类似物对原生动物寄生虫，特别是主要病原体墨西哥利什曼原虫和布氏锥虫。该系列在低至中等微摩尔范围内显示抗寄生虫活性，并建立了初步的结构-活性关系，其中4 '，N-3-二-（3，5-二甲基苯甲酰基）-取代的类似物显示出最突出的活性。利用一系列特别适应的细胞系，确定了这一系列类似物可能通过共同的靶标起作用。此外，杀锥虫和抗利什曼原虫活性之间的强相关性表明这一机制可能在两个物种之间共享。EC 50值不受T.布氏杆菌，表明这些尿苷类似物不直接作用于嘧啶核苷酸代谢的酶。与5-氟尿嘧啶缺乏交叉耐药性，也证明碳环类似物不是通过已知的尿嘧啶转运蛋白输入的，从而为这类核苷提供了新的见解。与目前的锥虫缺乏交叉耐药性，使这类化合物的进一步探索感兴趣。(C)2017爱思唯尔有限公司版权所有
Carbocyclic nucleoside analogues have a distinguished history as anti-infectious agents, including key antiviral agents. Toxicity was initially a concern but this was reduced by the introduction of 5'-nor variants. Here, we report the result of our preliminary screening of a series of 5'-norcarbocyclic uridine analogues against protozoan parasites, specifically the major pathogens Leishmania mexicana and Trypanosoma brucei. The series displayed antiparasite activity in the low to mid-micromolar range and establishes a preliminary structure-activity relationship, with the 4',N-3-di-(3,5-dimethylbenzoyl)-substituted analogues showing the most prominent activity. Utilizing an array of specially adapted cell lines, it was established that this series of analogues likely act through a common target. Moreover, the strong correlation between the trypanocidal and anti-leishmanial activities indicates that this mechanism is likely shared between the two species. EC50 values were unaffected by the disabling of pyrimidine biosynthesis in T. brucei, showing that these uridine analogues do not act directly on the enzymes of pyrimidine nucleotide metabolism. The lack of cross-resistance with 5-fluorouracil, also establishes that the carbocyclic analogues are not imported through the known uracil transporters, thus offering forth new insights for this class of nucleosides. The lack of cross-resistance with current trypanocides makes this compound class interesting for further exploration. (C) 2017 Elsevier Ltd. All rights reserved.