Zaleskaya-Hernik Marta, Salam Rayhanus, González Mario J, Wilczek Marcin, Dobrzycki Łukasz, Busschaert Nathalie, Romański Jan
Faculty of Chemistry, University of Warsaw Pasteura 1 Warsaw PL 02-093 Poland
Department of Chemistry, Tulane University New Orleans Louisiana 70118 USA
Chem Sci. 2025 Mar 18;16(16):6982-6990. doi: 10.1039/d5sc00866b. eCollection 2025 Apr 16.
Misregulation of transmembrane ion transport in biological systems has been linked to a variety of diseases. As a result, supramolecular chemists have been trying to develop small molecules that facilitate the transmembrane transport of several ionic species. However, ion transport by small molecules is a passive process and needs to be overall charge neutral (, when an ion is transported across a membrane, another ion needs to be transported as well to avoid charge separation). Ion pair receptors could therefore have great potential as transmembrane ion transporters because they can facilitate transport of an overall neutral species. Furthermore, ditopic ion pair receptors also have the potential to transport biologically important zwitterionic species, such as amino acids. In this manuscript, we report the synthesis of a series of ditopic receptors based on squaramides as the anion binding unit and 18-crown-6 as the cation binding unit. UV-vis and NMR titrations revealed that these compounds can bind a variety of chloride salts, especially KCl. Furthermore, liquid-liquid extractions and transport experiments using bulk liquid membranes and liposomes indicate that these ditopic receptors are capable of transporting chloride salts and hydrophilic amino acids. In fact, compound 5 was even able to facilitate the transport of amino acids with charged side chains at physiological pH (arginine and glutamate), making it the first example of a small molecule that can transport these highly polar and charge-dense species. These findings open up the possibility of using these receptors in a wide range of biological applications.
生物系统中跨膜离子转运的失调与多种疾病有关。因此，超分子化学家一直在尝试开发能够促进多种离子物种跨膜运输的小分子。然而，小分子介导的离子运输是一个被动过程，且需要整体电荷中性（即当一个离子跨膜运输时，另一个离子也需要被运输以避免电荷分离）。因此，离子对受体作为跨膜离子转运体具有巨大潜力，因为它们能够促进整体中性物种的运输。此外，双位点离子对受体还有运输生物重要两性离子物种（如氨基酸）的潜力。在本论文中，我们报道了一系列基于方酰胺作为阴离子结合单元和18-冠-6作为阳离子结合单元的双位点受体的合成。紫外-可见光谱和核磁共振滴定表明，这些化合物能够结合多种氯化物盐，尤其是氯化钾。此外，使用本体液膜和脂质体进行的液-液萃取和运输实验表明，这些双位点受体能够运输氯化物盐和亲水性氨基酸。事实上，化合物5甚至能够在生理pH值下促进带电荷侧链氨基酸（精氨酸和谷氨酸）的运输，使其成为能够运输这些高极性和电荷密集型物种的小分子的首个实例。这些发现为在广泛的生物应用中使用这些受体开辟了可能性。
