Cuffaro Doretta, Di Leo Riccardo, Ciccone Lidia, Nocentini Alessio, Supuran Claudiu T, Nuti Elisa, Rossello Armando
Department of Pharmacy, University of Pisa, Pisa, Italy.
Department of Neurofarba, University of Florence, Sesto Fiorentino, Italy.
J Enzyme Inhib Med Chem. 2023 Dec;38(1):2164574. doi: 10.1080/14756366.2022.2164574.
Carbonic anhydrases (CAs) are widespread metalloenzymes which catalyse the reversible hydration of carbon dioxide (CO) to bicarbonate (HCO) and a proton, relevant in many physiological processes. In the last few years, the involvement of CA activation in different metabolic pathways in the human brain addressed the research to the discovery of novel CA activators. Here, a new series of isoxazoline-based amino alcohols as CA activators was investigated. The synthesis and the CA activating effects towards four human CA isoforms expressed in the human brain, that are hCAs I, II, IV and VII, were reported. The best results were obtained for the (methyl)-isoxazoline-amino alcohols and with K values in the submicromolar range (0.52-0.86 µM) towards hCA VII, and a good selectivity over hCA I. Being hCA VII involved in brain function and metabolism, the newly identified CA activators might be promising hit compounds with potential therapeutic applications in ageing, epilepsy or neurodegeneration.
碳酸酐酶（CAs）是广泛存在的金属酶，可催化二氧化碳（CO）可逆水合生成碳酸氢根（HCO）和质子，这一过程在许多生理过程中都很重要。在过去几年中，碳酸酐酶激活在人类大脑不同代谢途径中的作用促使研究人员致力于发现新型碳酸酐酶激活剂。在此，研究了一系列基于异恶唑啉的新型氨基醇作为碳酸酐酶激活剂。报道了它们的合成以及对人类大脑中表达的四种人类碳酸酐酶同工型（即hCAs I、II、IV和VII）的碳酸酐酶激活作用。（甲基）-异恶唑啉-氨基醇 和 对hCA VII的K值在亚微摩尔范围内（0.52 - 0.86 µM），并对hCA I具有良好的选择性，取得了最佳结果。鉴于hCA VII参与大脑功能和代谢，新发现的碳酸酐酶激活剂可能是有前景的先导化合物，在衰老、癫痫或神经退行性疾病方面具有潜在的治疗应用价值。
