The key role of heme to trigger the antimalarial activity of trioxanes
The key role of heme to trigger the antimalarial activity of trioxanes
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DOI：
10.1016/j.ccr.2004.12.022
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发表时间：
2005-09-01
影响因子：
20.6
通讯作者：
Meunier, B
中科院分区：
文献类型：
--
作者：
Robert, A;Benoit-Vical, F;Meunier, B
青蒿素是一种有效的抗疟药物，含有1,2,4-三氧环，在体外和体内都能使血红素烷基化，产生共价血红素-青蒿素偶联产物。低价铁(H)原卟啉- ix是血红蛋白的假基，通过球内电子转移诱导青蒿素的过氧化物键均解。生成的烷氧基自由基被迅速重排为c中心自由基，从而有效地在中间位上烷基化血红素大环。因此，血红素既是青蒿素的激活剂又是其靶点。在这一作用机制的基础上，合成了一个新的以过氧化物为基础的抗疟药物家族，命名为trioxaquines (R)。三甲喹是由具有烷基化能力的三氧环与喹啉共价结合而成的，喹啉很容易穿透感染红细胞。几种三氯喹在体外以纳摩尔浓度对氯喹耐药疟疾寄生虫有活性，口服剂量为20-50 mg/kg可有效治愈感染小鼠。(c) 2005年Elsevier B.V.出版
Artemisinin is an efficient antimalarial drug containing a 1,2,4-trioxane, which is able to alkylate heme both in vitro and in vivo, giving rise to covalent heme-artemisinin coupling products. The low valent iron(H) protoporphyrin-IX, which is the prosthetic group of hemoglobin, induces the homolysis of the peroxide bond of artemisinin by an inner-sphere electron transfer. The generated alkoxy radical is quickly rearranged to a C-centered radical, which efficiently alkylates the heme macrocycle at meso positions. Heme is therefore both the activating agent and the target of artemisinin.On the basis of this mechanism of action, a new family of peroxide-based antimalarials named trioxaquines (R) has been synthesized. Trioxaquines are made by the covalent attachment of a trioxane, having alkylating ability, to a quinoline, known to easily penetrate within infected erythrocytes. Several trioxaquines are active in vitro on chloroquine resistant malaria parasite at nanomolar concentration, and are efficient by oral route to cure infected mice at 20-50 mg/kg. (c) 2005 Published by Elsevier B.V.