Alkoxide coordination of iron(III) protoporphyrin IX by antimalarial quinoline methanols: a key interaction observed in the solid-state and solution
Alkoxide coordination of iron(III) protoporphyrin IX by antimalarial quinoline methanols: a key interaction observed in the solid-state and solution
复制标题
DOI：
10.1039/c5dt02671g
复制
发表时间：
2015-01-01
影响因子：
4
通讯作者：
de Villiers, Katherine A.
中科院分区：
文献类型：
--
作者：
Gildenhuys, Johandie;Sammy, Chandre J.;de Villiers, Katherine A.
喹啉甲醇抗疟疾药物甲氟喹是金鸡纳生物碱、奎宁和奎尼丁的结构类似物。我们已经阐明了单晶X-射线衍射结构的外消旋间苯二甲喹和铁原卟啉IX（Fe（III）PPIX）之间形成的配合物，并表明，醇盐协调是一个关键的相互作用在固态。质谱证实了奎宁，奎尼丁和甲氟喹的铁（III）PPIX在乙腈中的配位络合物的存在。通过扩展X射线吸收精细结构（EXAFS）光谱测定的奎宁和奎尼丁络合物中的铁（III）-O键的长度明确地证实喹啉甲醇化合物与Fe（III）PPIX的配位通过其苄醇盐官能团在非水非质子溶液中发生。紫外-可见分光光度滴定的低自旋双吡啶基-Fe（III）PPIX复合物与每个喹啉甲醇化合物的结果在一个单一的吡啶分子的位移和随后形成的六配位吡啶-Fe（III）PPIX-药物复合物。我们建议，形成的药物-Fe（III）PPIX配合物有利于在非水环境中，如发现在脂质体或膜中的疟疾寄生虫，和它们的存在可能有助于疟原虫色素抑制或其他毒性作用，最终导致寄生虫死亡的机制。在任何一种情况下，协调都是设计新型抗疟候选药物时要考虑的一个关键相互作用。
The quinoline methanol antimalarial drug mefloquine is a structural analogue of the Cinchona alkaloids, quinine and quinidine. We have elucidated the single crystal X-ray diffraction structure of the complexes formed between racemic erythro mefloquine and ferriprotoporphyrin IX (Fe(III) PPIX) and show that alkoxide coordination is a key interaction in the solid-state. Mass spectrometry confirms the existence of coordination complexes of quinine, quinidine and mefloquine to Fe(III) PPIX in acetonitrile. The length of the iron(III)-O bond in the quinine and quinidine complexes as determined by Extended X-ray Absorption Fine Structure (EXAFS) spectroscopy unequivocally confirms that coordination of the quinoline methanol compounds to Fe(III) PPIX occurs in non-aqueous aprotic solution via their benzylic alkoxide functional group. UV-visible spectrophotometric titrations of the low-spin bis-pyridyl-Fe(III) PPIX complex with each of the quinoline methanol compounds results in the displacement of a single pyridine molecule and subsequent formation of a six-coordinate pyridine-Fe(III) PPIX-drug complex. We propose that formation of the drug-Fe(III) PPIX coordination complexes is favoured in a non-aqueous environment, such as that found in lipid bodies or membranes in the malaria parasite, and that their existence may contribute to the mechanism of haemozoin inhibition or other toxicity effects that lead ultimately to parasite death. In either case, coordination is a key interaction to be considered in the design of novel antimalarial drug candidates.