Comparison of the Reactivity of Antimalarial 1,2,4,5-Tetraoxanes with 1,2,4-Trioxolanes in the Presence of Ferrous Iron Salts, Heme, and Ferrous Iron Salts/Phosphatidylcholine
Comparison of the Reactivity of Antimalarial 1,2,4,5-Tetraoxanes with 1,2,4-Trioxolanes in the Presence of Ferrous Iron Salts, Heme, and Ferrous Iron Salts/Phosphatidylcholine
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DOI：
10.1021/jm200768h
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发表时间：
2011-10-13
影响因子：
7.3
通讯作者：
O'Neill, Paul M.
中科院分区：
文献类型：
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作者：
Bousejra-El Garah, Fatima;Wong, Michael He-Long;O'Neill, Paul M.
二螺-1,2,4,5-四恶烷和1,2,4-三氧戊环由于其结构简单、稳定性好和令人印象深刻的抗疟活性而代表了有吸引力的合成抗疟过氧化物类别。我们研究了一系列有效的酰胺官能化四恶烷与葡萄糖酸 Fe(II)、FeSO4、FeSO4/TEMPO、FeSO4/磷脂酰胆碱和血红素的反应性，以了解其潜在的生物活化机制，并将结果与相应的 1,2,4-三氧戊环进行比较。自旋捕获实验表明，Fe(II) 介导的过氧化物活化四氧杂环己烷产生初级和次级 C 自由基中间体。在芬顿反应条件下，四氧杂环己烷和三氧戊环与磷脂酰胆碱（寄生虫消化液泡膜中存在的主要不饱和脂质）的反应表明，两种内过氧化物在磷脂氧化方面具有与青蒿素不同的共同反应性。值得注意的是，当四恶烷在血红素存在下进行生物活化时，仅观察到次级以 C 为中心的自由基，该自由基顺利地产生区域异构药物衍生的血红素加合物。这些四恶烷烷基化卟啉环的能力也得到了 (FeTPP)-T-II 和 (MnTPP)-T-II 的证实，并进行了对接研究以合理化在烷基化过程中观察到的区域选择性。这里观察到的血红素烷基化和广泛的脂质过氧化的有效过程可能在这两类重要的合成内过氧化物抗疟药的作用机制中发挥作用。
Dispiro-1,2,4,5-tetraoxanes and 1,2,4-trioxolanes represent attractive classes of synthetic antimalarial peroxides due to their structural simplicity, good stability, and impressive antimalarial activity. We investigated the reactivity of a series of potent amide functionalized tetraoxanes with Fe(II)gluconate, FeSO4, FeSO4/TEMPO, FeSO4/phosphatidylcholine, and heme to gain knowledge of their potential mechanism of bioactivation and to compare the results with the corresponding 1,2,4-trioxolanes. Spin-trapping experiments demonstrate that Fe(II)-mediated peroxide activation of tetraoxanes produces primary and secondary C-radical intermediates. Reaction of tetraoxanes and trioxolanes with phosphatidylcholine, a predominant unsaturated lipid present in the parasite digestive vacuole membrane, under Fenton reaction conditions showed that both endoperoxides share a common reactivity in terms of phospholipid oxidation that differs with that of artemisinin. Significantly, when tetraoxanes undergo bioactivation in the presence of heme, only the secondary C-centered radical is observed, which smoothly produces regioisomeric drug derived-heme adducts. The ability of these tetraoxanes to alkylate the porphyrin ring was also confirmed with (FeTPP)-T-II and (MnTPP)-T-II, and docking studies were performed to rationalize the regioselectivity observed in the alkylation process. The efficient process of heme alkylation and extensive lipid peroxidation observed here may play a role in the mechanism of action of these two important classes of synthetic endoperoxide antimalarial.