Carbocyclic 6-benzylthioinosine analogues as subversive substrates of Toxoplasma gondii adenosine kinase: Biological activities and selective toxicities
Carbocyclic 6-benzylthioinosine analogues as subversive substrates of Toxoplasma gondii adenosine kinase: Biological activities and selective toxicities
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DOI：
10.1016/j.bcp.2010.06.001
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发表时间：
2010-10-01
影响因子：
5.8
通讯作者：
el Kouni, Mahmoud H.
中科院分区：
文献类型：
--
作者：
Al Safarjalani, Omar N.;Rais, Reem H.;el Kouni, Mahmoud H.
弓形虫腺苷激酶(EC2.7.1.20)是该寄生虫体内腺苷代谢的主要途径。该酶比弓形虫中回收嘌呤的任何其他酶都具有更高的活性，已被确定为治疗弓形虫病的潜在化疗靶点。几种6-苄基硫代肌苷已经被鉴定为弓形虫的颠覆性底物，但不是人的腺苷激酶。因此，这些化合物优先被代谢成它们各自的核苷酸，并对寄生虫产生选择性毒性，但对其宿主没有。在本研究中，我们报告了几种碳环6-苄基硫代肌苷的代谢测试，以及它们在细胞培养中作为抗弓形虫药物的有效性。所有的碳环6-苄基硫代肌苷类似物都被代谢成它们的5‘-单磷酸衍生物，尽管程度不同。这些结果表明，这些化合物不仅是弓形虫的配体，也是弓形虫腺苷激酶的底物。所有的碳环6-苄基硫代肌苷类似物都显示出对野生型寄生虫的选择性抗弓形体作用，但不包括缺乏腺苷激酶的突变体。这些结果表明，糖的氧原子对底物结合不是关键的。这些化合物的功效随其苯环上取代的位置和性质而不同。此外，这些类似物都没有表现出寄主毒性。最好的化合物为碳环6-(对甲氧基苄硫基)肌苷(IC50=11.9mU)、碳环6-(对甲氧基苄硫基)肌苷(IC50=12.1mU)和碳环6-(对甲氧基苄硫基)肌苷(IC50=12.8mU)。与相应的6-苄基硫代肌苷类似物相比，这些化合物的疗效提高了约1.5倍(Rais等人，Biochem Pharmacol 2005：69：1409-19[29])。这一结果进一步证实了弓形虫的腺苷激酶是一个很好的化疗靶点，碳环6-苄基硫代肌苷是潜在的抗弓形虫药物。(C)2010 Elsevier Inc.保留所有权利。
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. Several 6-benzylthioinosines have already been identified as subversive substrates of the T. gondii but not human adenosine kinase. Therefore, these compounds are preferentially metabolized to their respective nucleotides and become selectively toxic against the parasites but not its host. In the present study, we report the testing of the metabolism of several carbocyclic 6-benzylthioinosines, as well as their efficacy as anti-toxoplasmic agents in cell culture. All the carbocyclic 6-benzylthioinosine analogues were metabolized to their 5'-monophosphate derivatives, albeit to different degrees. These results indicate that these compounds are not only ligands but also substrates of T. gondii adenosine kinase. All the carbocyclic 6-benzylthioinosine analogues showed a selective anti-toxoplasmic effect against wild type parasites, but not mutants lacking adenosine kinase. These results indicate that the oxygen atom of the sugar is not critical for substrate binding. The efficacy of these compounds varied with the position and nature of the substitution on their phenyl ring. Moreover, none of these analogues exhibited host toxicity. The best compounds were carbocyclic 6-(p-methylbenzylthio)inosine (IC50 = 11.9 mu M), carbocyclic 6-(p-methoxybenzylthio)inosine (IC50 = 12.1 mu M), and carbocyclic 6-(p-methoxycarbonylbenzylthio)inosine (IC50 = 12.8 mu M). These compounds have about a 1.5-fold better efficacy relative to their corresponding 6-benzylthioinosine analogues (Rais et al., Biochem Pharmacol 2005:69:1409-19 [29]). The results further confirm that T. gondii adenosine kinase is an excellent target for chemotherapy and that carbocyclic 6-benzylthioinosines are potential anti-toxoplasmic agents. (C) 2010 Elsevier Inc. All rights reserved.