Solomonov Inna, Osipova Maria, Feldman Yishay, Baehtz Carsten, Kjaer Kristian, Robinson Ian K, Webster Grant T, McNaughton Don, Wood Bayden R, Weissbuch Isabelle, Leiserowitz Leslie
Department of Materials and Interfaces, The Weizmann Institute of Science, 76100-Rehovot, Israel.
J Am Chem Soc. 2007 Mar 7;129(9):2615-27. doi: 10.1021/ja0674183. Epub 2007 Feb 10.
The morphology of micrometer-sized beta-hematin crystals (synthetic malaria pigment) was determined by TEM images and diffraction, and by grazing incidence synchrotron X-ray diffraction at the air-water interface. The needle-like crystals are bounded by sharp {100} and {010} side faces, and capped by {011} and, to a lesser extent, by {001} end faces, in agreement with hemozoin (malaria pigment) crystals. The beta-hematin crystals grown in the presence of 10% chloroquine or quinine took appreciably longer to precipitate and tended to be symmetrically tapered toward both ends of the needle, due to stereoselective additive binding to {001} or {011} ledges. Evidence, but marginal, is presented that additives reduce crystal mosaic domain size along the needle axis, based on X-ray powder diffraction data. Coherent grazing exit X-ray diffraction suggests that the mosaic domains are smaller and less structurally stable than in pure crystals. IR-ATR and Raman spectra indicate molecular based differences due to a modification of surface and bulk propionic acid groups, following additive binding and a molecular rearrangement in the environment of the bulk sites poisoned by occluded quinoline. These results provided incentive to examine computationally whether hemozoin may be a target of antimalarial drugs diethylamino-alkoxyxanthones and artemisinin. A variation in activity of the former as a function of the alkoxy chain length is correlated with computed binding energy to {001} and {011} faces of beta-hematin. A model is proposed for artemisinin activity involving hemozoin nucleation inhibition via artemisinin-beta-hematin adducts bound to the principal crystal faces. Regarding nucleation of hemozoin inside the digestive vacuole of the malaria parasite, nucleation via the vacuole's membranous surface is proposed, based on a reported hemozoin alignment. As a test, a dibehenoyl-phosphatidylcholine monolayer transferred onto OTS-Si wafer nucleated far more beta-hematin crystals, albeit randomly oriented, than a reference OTS-Si.
通过透射电子显微镜（TEM）图像和衍射，以及在气-水界面的掠入射同步加速器X射线衍射，确定了微米级β-血红素晶体（合成疟疾色素）的形态。针状晶体由尖锐的{100}和{010}侧面界定，并由{011}端面封顶，在较小程度上由{001}端面封顶，这与疟色素晶体一致。在10%氯喹或奎宁存在下生长的β-血红素晶体沉淀明显需要更长时间，并且由于立体选择性添加剂与{001}或{011}台阶的结合，晶体倾向于向针的两端对称变细。基于X射线粉末衍射数据，有证据（但很有限）表明添加剂会减小晶体沿针轴的镶嵌域尺寸。相干掠出X射线衍射表明，镶嵌域比纯晶体中的更小，结构稳定性更低。红外衰减全反射（IR-ATR）和拉曼光谱表明，由于添加剂结合后表面和本体丙酸基团的修饰以及被封闭喹啉毒害的本体位点环境中的分子重排，存在基于分子的差异。这些结果促使人们通过计算研究疟色素是否可能是抗疟药物二乙氨基烷氧基呫吨酮和青蒿素的靶点。前者活性随烷氧基链长度的变化与计算得到的与β-血红素{001}和{011}面的结合能相关。提出了一个关于青蒿素活性的模型，该模型涉及通过与主要晶面结合的青蒿素-β-血红素加合物抑制疟色素成核。关于疟原虫消化泡内疟色素的成核，基于报道的疟色素排列，提出了通过液泡膜表面成核的观点。作为一项测试，转移到OTS-Si晶片上的二山嵛酰磷脂酰胆碱单层比参考OTS-Si晶片能使更多的β-血红素晶体成核，尽管晶体取向是随机的。
