Inhibition of heme detoxification processes underlies the antimalarial activity of terpene isonitrile compounds from marine sponges
Inhibition of heme detoxification processes underlies the antimalarial activity of terpene isonitrile compounds from marine sponges
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DOI：
10.1021/jm0010724
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发表时间：
2001-03-15
影响因子：
7.3
通讯作者：
Tilley, L
中科院分区：
文献类型：
--
作者：
Wright, AD;Wang, HQ;Tilley, L
从海洋海绵中分离出的一系列萜烯异腈类化合物此前已被证明具有抗疟疾活性。使用3D-QSAR和受体建模方法对这些异腈进行的分子建模研究表明，建模的分子可以用来生成与实验得出的生物活性一致的药效团假说。研究还表明，其中一个模拟化合物，二异氰烷(4)，以及轴异腈-3(2)，都具有很强的抗疟疾活性，通过与血红素(FP)铁形成配位络合物而与FP相互作用。此外，在模拟疟疾寄生虫环境的条件下，这些化合物被证明可以抑制FP被隔离到P-血红素中，并防止过氧化和谷胱甘肽介导的FP破坏。相比之下，两个模拟的二萜异腈，7-异氰胺-11(20)，15-二烯(12)和7-isocyano-15-isothiocyanatoamphilecta-11(20)-ene(13)，没有显示出抗疟疾活性，在这些FP解毒试验中也显示出很少的抑制活性。这些研究表明，活性异腈类化合物，如喹啉类抗疟药，通过阻止FP解毒而发挥其抗疟原虫活性。对二异氰基二环己烷(4)和异氰酸酯-3(2)进行的分子动力学模拟可以区分它们与FP的不同结合。
A series of terpene isonitriles, isolated from marine sponges, have previously been shown to exhibit antimalarial activities. Molecular modeling studies employing 3D-QSAR with receptor modeling methodologies performed with these isonitriles showed that the modeled molecules could be used to generate a pharmacophore hypothesis consistent with the experimentally derived biological activities. It was also shown that one of the modeled compounds, diisocyanoadociane (4), as well as axisonitrile-3 (2), both of which have potent antimalarial activity, interacts with heme (FP) by forming a coordination complex with the FP iron. Furthermore, these compounds were shown to inhibit sequestration of FP into P-hematin and to prevent both the peroxidative and glutathione-mediated destruction of FP under conditions designed to mimic the environment within the malaria parasite. By contrast, two of the modeled diterpene isonitriles, 7-isocyanoamphilecta-11(20),15-diene (12) and 7-isocyano-15-isothiocyanatoamphilecta-11(20)-ene (13), that displayed little antimalarial activity also showed little inhibitory activity in these FP detoxification assays. These studies suggest that the active isonitrile compounds, like the quinoline antimalarials, exert their antiplasmodial activity by preventing FP detoxification. Molecular dynamics simulations performed with diisocyanoadociane (4) and axisonitrile-3 (2) allowed their different binding to FP to be distinguished.