Natural Sesquiterpene Lactones of the 4,15-iso-Atriplicolide Type are Inhibitors of Trypanothione Reductase
Natural Sesquiterpene Lactones of the 4,15-iso-Atriplicolide Type are Inhibitors of Trypanothione Reductase
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DOI：
10.3390/molecules24203737
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发表时间：
2019-10-01
期刊：
影响因子：
4.6
通讯作者：
Schmidt, Thomas J.
中科院分区：
文献类型：
--
作者：
Lenz, Mairin;Krauth-Siegel, R. Luise;Schmidt, Thomas J.
在我们对倍半萜内酯（STL）的抗锥虫潜力进行研究的过程中，我们最近报道了4，15-iso-Atripliclicantiglate的异常强活性，其对东非人类锥虫（HAT）的病原体布氏罗得西亚锥虫的IC 50值为15 nM。由于已知STL经常与其生物靶标相互作用（例如，在抗炎和抗肿瘤活性中）通过共价修饰生物亲核体-最显著的是蛋白质中的游离半胱氨酸巯基-直接假设这些化合物可能干扰锥虫的锥虫硫酮相关解毒系统。该系统严重依赖于二巯基锥虫硫酮（T（SH）（2））形式的巯基以及参与锥虫硫酮代谢和体内平衡的酶的活性中心。事实上，我们在本研究中发现，4，15-iso-atripliclactintiglate及其结构同源物，相应的甲基丙烯酸酯和异丁酸酯，是锥虫硫酮还原酶（TR）的抑制剂，该酶为寄生虫保持T（SH）（2）在二硫醇状态。TR抑制活性被证明是时间依赖性的和不可逆的。非常有趣的是，在还测试的具有不同核心结构的几种另外的STL中，没有一种在显著水平上抑制TR。因此，4，15-异-阿替普利酯的TR抑制作用似乎对这种特定类型的呋喃基向日葵内酯型STL具有特异性。一些结构-活性关系已经可以推断的基础上报告的数据在这里，这可能作为出发点，寻找进一步的，可能更有效的，TR抑制剂。
In the course of our investigations on the antitrypanosomal potential of sesquiterpene lactones (STL), we have recently reported on the exceptionally strong activity of 4,15-iso-Atriplicolide tiglate, which demonstrated an IC50 value of 15 nM against Trypanosoma brucei rhodesiense, the etiologic agent responsible for East African human trypanosomiasis (HAT). Since STLs are known to often interact with their biological targets (e.g., in anti-inflammatory and anti-tumor activity) by means of the covalent modification of biological nucleophiles-most prominently free cysteine thiol groups in proteins-it was a straightforward assumption that such compounds might interfere with the trypanothione-associated detoxification system of trypanosomes. This system heavily relies on thiol groups in the form of the dithiol trypanothione (T(SH)(2)) and in the active centers of enzymes involved in trypanothione metabolism and homeostasis. Indeed, we found in the present study that 4,15-iso-atriplicolide tiglate, as well as its structural homologues, the corresponding methacrylate and isobutyrate, are inhibitors of trypanothione reductase (TR), the enzyme serving the parasites to keep T(SH)(2) in the dithiol state. The TR inhibitory activity was demonstrated to be time-dependent and irreversible. Quite interestingly, of the several further STLs with different core structures that were also tested, none inhibited TR at a significant level. Thus, the TR inhibitory effect by the 4,15-iso-atriplicolide esters appears to be specific for this particular type of furanoheliangolide-type STL. Some structure-activity relationships can already be deduced on the basis of the data reported here, which may serve as the starting point for searching further, possibly more potent, TR inhibitors.