Omar A M, Mahran M A, Ghatge M S, Chowdhury N, Bamane F H A, El-Araby M E, Abdulmalik O, Safo M K
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Alsulaymanyah, Jeddah 21589, Saudi Arabia.
Org Biomol Chem. 2015 Jun 14;13(22):6353-70. doi: 10.1039/c5ob00367a.
Aromatic aldehydes and ethacrynic acid (ECA) exhibit antipolymerization properties that are beneficial for sickle cell disease therapy. Based on the ECA pharmacophore and its atomic interaction with hemoglobin, we designed and synthesized several compounds - designated as KAUS (imidazolylacryloyl derivatives) - that we hypothesized would bind covalently to βCys93 of hemoglobin and inhibit sickling. The compounds surprisingly showed weak allosteric and antisickling properties. X-ray studies of hemoglobin in complex with representative KAUS compounds revealed an unanticipated mode of Michael addition between the β-unsaturated carbon and the N-terminal αVal1 nitrogen at the α-cleft of hemoglobin, with no observable interaction with βCys93. Interestingly, the compounds exhibited almost no reactivity with the free amino acids, L-Val, L-His and L-Lys, but showed some reactivity with both glutathione and L-Cys. Our findings provide a molecular level explanation for the compounds biological activities and an important framework for targeted modifications that would yield novel potent antisickling agents.
芳香醛和依他尼酸（ECA）具有抗聚合特性，这对镰状细胞病治疗有益。基于ECA药效团及其与血红蛋白的原子相互作用，我们设计并合成了几种化合物——命名为KAUS（咪唑基丙烯酰衍生物）——我们推测它们会与血红蛋白的βCys93共价结合并抑制镰变。令人惊讶的是，这些化合物表现出较弱的变构和抗镰变特性。血红蛋白与代表性KAUS化合物复合物的X射线研究揭示了β-不饱和碳与血红蛋白α-裂隙处N端αVal1氮之间意外的迈克尔加成模式，未观察到与βCys93的相互作用。有趣的是，这些化合物与游离氨基酸L-缬氨酸、L-组氨酸和L-赖氨酸几乎没有反应性，但与谷胱甘肽和L-半胱氨酸都有一些反应性。我们的研究结果为这些化合物的生物活性提供了分子水平的解释，并为产生新型强效抗镰变剂的靶向修饰提供了重要框架。
