Structural analysis of the anti-malaria active agent chloroquine under physiological conditions
Structural analysis of the anti-malaria active agent chloroquine under physiological conditions
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DOI：
10.1021/jp065136j
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发表时间：
2007-02-22
影响因子：
3.3
通讯作者：
Popp, Juergen
中科院分区：
文献类型：
--
作者：
Frosch, Torsten;Schmitt, Michael;Popp, Juergen
应用紫外共振拉曼光谱对生理条件下重要抗疟药物氯喹的分子振动进行了选择性增强。氯喹的共振拉曼光谱在721 cm（-1）处的拉曼共振增强模式下，可以清楚地区分血液pH值和疟原虫酸性食物泡pH值。这些振动被分配到氯喹侧链的-（CH 2）（n）-摇摆模式，并预计将受到氯喹的质子化。此外，属于喹啉环的振动（对疟原虫色素的π-π相互作用很重要）被共振增强，并且可以选择性地进行研究。通过DFT计算进行了令人信服的模式分配。计算结果表明，氯喹的不同质子化状态对分子的振动模式、几何构型和轨道有显著的影响。这些结果对于氯喹在疟原虫酸性食物泡内的拉曼光谱定位、氯喹与生物靶分子血红素和疟原虫色素的π-π相互作用以及氯喹在此对接过程中的质子化状态的研究具有重要意义。弱碱性氯喹的质子化被认为是疟原虫酸性食物泡内积累的关键，也是对这种药物产生抗性的对象。
UV resonance Raman spectroscopy was applied for a selective enhancement of molecular vibrations of the important antimalarial chloroquine under physiological conditions. The resonance Raman spectra of chloroquine at pH values resembling the pH value of blood and the pH value of the acid food vacuole of plasmodium can unambiguously be distinguished via Raman resonantly enhanced mode at 721 cm(-1). These vibrations are assigned to -(CH2)(n)- rocking mode of the chloroquine side chain and are expected to be influenced by protonation of chloroquine. Furthermore, vibrations belonging to the quinoline ring (important for pi-pi-interactions to hemozoin) are resonantly enhanced and can be studied selectively. A convincing mode assignment was performed by means of DFT calculations. These calculations proved that the different protonation states of chloroquine remarkably influence various vibrational modes, the molecular geometry, and molecular orbitals. The presented results are of significant relevance for a Raman spectroscopical localization of chloroquine inside the acid food vacuole of plasmodium, the study of pi-pi-interactions of chloroquine to the biological target molecules hematin and hemozoin and the protonation state of chloroquine during this docking process. The protonation of the weak base chloroquine is considered to be crucial for an accumulation inside the acid food vacuole of plasmodium and an object for resistances against this drug.