Maslowska-Jarzyna Krystyna, Korczak Maria L, Chmielewski Michał J
Faculty of Chemistry, Biological and Chemical Research Centre, University of Warsaw, Warsaw, Poland.
Front Chem. 2021 May 20;9:690035. doi: 10.3389/fchem.2021.690035. eCollection 2021.
Artificial chloride transporters have been intensely investigated in view of their potential medicinal applications. Recently, we have established 1,8-diamidocarbazoles as a versatile platform for the development of active chloride carriers. In the present contribution, we investigate the influence of various electron-withdrawing substituents in positions 3 and 6 of the carbazole core on the chloride transport activity of these anionophores. Using lucigenin assay and large unilamellar vesicles as models, the 3,6-dicyano- and 3,6-dinitro- substituted receptors were found to be highly active and perfectly deliverable chloride transporters, with EC value as low as 22 nM for the Cl/NO exchange. Mechanistic studies revealed that diamidocarbazoles form 1:1 complexes with chloride in lipid bilayers and facilitate chloride/nitrate exchange by carrier mechanism. Furthermore, owing to its increased acidity, the 3,6-dinitro- substituted receptor acts as a pH-switchable transporter, with physiologically relevant apparent pK of 6.4.
鉴于人工氯化物转运体的潜在医学应用价值，人们对其进行了深入研究。最近，我们已将1,8 - 二氨基咔唑确立为开发活性氯化物载体的通用平台。在本论文中，我们研究了咔唑核心3位和6位上各种吸电子取代基对这些阴离子载体氯化物转运活性的影响。以光泽精测定法和大单层囊泡为模型，发现3,6 - 二氰基和3,6 - 二硝基取代的受体是高活性且极易实现的氯化物转运体，其Cl⁻/NO₃⁻交换的EC值低至22 nM。机理研究表明，二氨基咔唑在脂质双层中与氯化物形成1:1配合物，并通过载体机制促进氯化物/硝酸盐交换。此外，由于其酸度增加，3,6 - 二硝基取代的受体可作为pH可切换的转运体，其生理相关的表观pK为6.4。
