Egan Timothy J, Ncokazi Kanyile K
Department of Chemistry, University of Cape Town, Private Bag, Rondebosch 7701, South Africa.
J Inorg Biochem. 2004 Jan;98(1):144-52. doi: 10.1016/j.jinorgbio.2003.09.007.
Enthalpy-entropy compensation in the interaction of quinoline antimalarials with ferriprotoporphyrin IX (Fe(III)PPIX) in 40% aqueous dimethyl sulfoxide (DMSO) has been compared with that in pure aqueous solution. The data indicate that the degree of desolvation and loss of conformational freedom is virtually identical in both systems. Taken together with previous findings showing that the molar free energies of association of these drugs with Fe(III)PPIX in both solvent systems are very similar, this suggests that the recognition site on the metalloporphyrin is comparable in both cases. This is despite the fact that Fe(III)PPIX exists as a dimer in aqueous solution, but is monomeric in 40% DMSO. Free energies of association of chloroquine, quinine and quinidine with Fe(III)PPIX are largely insensitive to the concentration of sodium perchlorate in 40% DMSO. This demonstrates that electrostatic interactions play only a minor role in the overall stability of these complexes under these conditions. Increasing DMSO concentration greatly weakens the interactions of chloroquine, amodiaquine, quinine, quinidine and 9-epiquinine with Fe(III)PPIX. This suggests that hydrophobic interaction plays a major role in the stability of these complexes. Further investigation of chloroquine has revealed that the free energy of association with Fe(III)PPIX also weakens as a function of decreasing solvent polarity in pure organic solvents. However, the free energies of association are weaker in the mixed aqueous solvent than in pure organic solvents. This indicates that dispersion and electrostatic interactions are relatively strong in the non-aqueous environment. The results demonstrate that any successful model of antimalarial drug-Fe(III)PPIX interactions will need to take both solvation and electrostatic factors into account.
在40%的二甲基亚砜（DMSO）水溶液中，喹啉类抗疟药与高铁原卟啉IX（Fe(III)PPIX）相互作用的焓-熵补偿已与纯水溶液中的情况进行了比较。数据表明，在这两个体系中，去溶剂化程度和构象自由度的损失几乎相同。结合先前的研究结果表明，在这两种溶剂体系中，这些药物与Fe(III)PPIX的缔合摩尔自由能非常相似，这表明在两种情况下，金属卟啉上的识别位点具有可比性。尽管事实上Fe(III)PPIX在水溶液中以二聚体形式存在，但在40%的DMSO中是单体形式。氯喹、奎宁和奎尼丁与Fe(III)PPIX的缔合自由能在很大程度上对40% DMSO中高氯酸钠的浓度不敏感。这表明在这些条件下，静电相互作用在这些配合物的整体稳定性中只起次要作用。增加DMSO浓度会大大削弱氯喹、阿莫地喹、奎宁、奎尼丁和9-表奎宁与Fe(III)PPIX的相互作用。这表明疏水相互作用在这些配合物的稳定性中起主要作用。对氯喹的进一步研究表明，在纯有机溶剂中，与Fe(III)PPIX的缔合自由能也会随着溶剂极性的降低而减弱。然而，在混合水溶液中的缔合自由能比在纯有机溶剂中弱。这表明在非水环境中，色散和静电相互作用相对较强。结果表明，任何成功的抗疟药物-Fe(III)PPIX相互作用模型都需要同时考虑溶剂化和静电因素。
