ACS Chem Biol. 2012 Apr 20;7(4):666-71. doi: 10.1021/cb200528z. Epub 2012 Feb 3.
The antimalarial properties of the Cinchona alkaloids quinine and quinidine have been known for decades. Surprisingly, 9-epiquinine and 9-epiquinidine are almost inactive. A lack of definitive structural information has precluded a clear understanding of the relationship between molecular structure and biological activity. In the current study, we have determined by single crystal X-ray diffraction the structures of the complexes formed between quinine and quinidine and iron(III) protoporphyrin IX (Fe(III)PPIX). Coordination of the alkaloid to the Fe(III) center is a key feature of both complexes, and further stability is provided by an intramolecular hydrogen bond formed between a propionate side chain of Fe(III)PPIX and the protonated quinuclidine nitrogen atom of either alkaloid. These interactions are believed to be responsible for inhibiting the incorporation of Fe(III)PPIX into crystalline hemozoin during its in vivo detoxification. It is also possible to rationalize the greater activity of quinidine compared to that of quinine.
奎宁和辛可宁等金鸡纳生物碱的抗疟特性已为人所知数十年。令人惊讶的是，9-表奎宁和 9-表辛可宁几乎没有活性。由于缺乏明确的结构信息，因此无法清楚了解分子结构与生物活性之间的关系。在目前的研究中，我们通过单晶 X 射线衍射确定了奎宁和辛可宁与铁（III）原卟啉 IX（Fe（III）PPIX）形成的配合物的结构。生物碱与 Fe（III）中心的配位是两个配合物的关键特征，通过 Fe（III）PPIX 的丙酸盐侧链和任一生物碱的质子化奎宁啶氮原子之间形成的分子内氢键提供了进一步的稳定性。这些相互作用被认为负责抑制 Fe（III）PPIX 在其体内解毒过程中掺入结晶疟色素。也可以合理地解释与奎宁相比，辛可宁的活性更高。
