6-Benzylthioinosine analogues as subversive substrate of Toxoplasma gondii adenosine kinase: activities and selective toxicities.
6-Benzylthioinosine analogues as subversive substrate of Toxoplasma gondii adenosine kinase: activities and selective toxicities.
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6-苄基硫代肌苷类似物作为弓形虫腺苷激酶的破坏性底物：活性和选择性毒性。
DOI：
10.1016/j.bcp.2005.02.017
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发表时间：
2005
期刊：
影响因子：
--
通讯作者：
elKouni,MahmoudH
中科院分区：
文献类型：
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作者：
Rais,ReemH;AlSafarjalani,OmarN;Yadav,Vikas;Guarcello,Vincenzo;Kirk,Marion;Chu,ChungK;Naguib,FardosNM;elKouni,MahmoudH
刚地弓形虫腺苷激酶（EC. 2. 7. 1. 20）是该寄生虫腺苷代谢的主要途径。该酶活性明显高于T.并已被确定为治疗弓形虫病的潜在化疗靶点。某些6-取代嘌呤核苷是T.弓形虫，而不是人类，腺苷激酶。因此，这些化合物优先代谢为它们各自的核苷酸，并对寄生虫而不是它们的宿主具有选择性毒性。本文报道了新合成的苄基苯环上具有不同取代基的6-苄基硫代肌苷类似物作为T.弓形虫腺苷激酶。这些化合物与T.弓形虫腺苷激酶和它们作为抗弓形虫剂的功效取决于它们苄基的苯环上各种取代基的性质和位置。对氰基-6-苄硫基肌苷和2，4-二氯-6-苄硫基肌苷是最好的配体。一般来说，苯环帕拉取代的类似物比Meta或邻位取代的类似物是更好的配体。对位取代的类似物的更好的结合归因于疏水性以及货车范德华相互作用的组合效应。6-苄基硫代肌苷类似物没有宿主毒性，但在细胞培养和动物模型中均显示出选择性抗弓形虫作用。这些结果进一步证实了弓形虫腺苷激酶是一个极好的化疗靶点，6-取代嘌呤核苷是潜在的选择性抗弓形虫药物
Toxoplasma gondii adenosine kinase (EC.2.7.1.20) is the major route of adenosine metabolism in this parasite. The enzyme is significantly more active than any other enzyme of the purine salvage in T. gondii and has been established as a potential chemotherapeutic target for the treatment of toxoplasmosis. Certain 6-substituted purine nucleosides act as subversive substrates of T. gondii, but not the human, adenosine kinase. Therefore, these compounds are preferentially metabolized to their respective nucleotides and become selectively toxic against the parasites but not their host. Herein, we report the testing of newly synthesized 6-benzylthioinosine analogues with various substituents on the phenyl ring of their benzyl group as subversive substrates of T. gondii adenosine kinases. The binding affinity of these compounds to T. gondii adenosine kinase and their efficacy as antitoxoplasmic agents varied depending on the nature and position of the various substituents on the phenyl ring of their benzyl group. p-Cyano-6-benzylthioinosine and 2,4-dichloro-6-benzylthioinosine were the best ligands. In general, analogues with substitution at the para position of the phenyl ring were better ligands than those with the same substitutions at the meta or ortho position. The better binding of the para-substituted analogues is attributed to the combined effect of hydrophobic as well as van der Waals interactions. The 6-benzylthioinosine analogues were devoid of host-toxicity but all showed selective anti-toxoplasmic effect in cell culture and animal models. These results further confirm that toxoplasma adenosine kinase is an excellent target for chemotherapy and that 6-substituted purine nucleosides are potential selective antitoxoplasmic agents