Akocak Suleyman, Lolak Nabih, Vullo Daniela, Durgun Mustafa, Supuran Claudiu T
a Department of Pharmaceutical Chemistry, Faculty of Pharmacy , Adiyaman University , Adiyaman , Turkey.
b NEUROFARBA Dept., Sezione di Scienze Farmaceutiche , Università degli Studi di Firenze , Florence , Italy.
J Enzyme Inhib Med Chem. 2017 Dec;32(1):1305-1312. doi: 10.1080/14756366.2017.1386660.
A series of 20 histamine Schiff base was synthesised by reaction of histamine, a well known carbonic anhydrase (CA, E.C 4.2.2.1.) activator pharmacophore, with substituted aldehydes. The obtained histamine Schiff bases were assayed as activators of five selected human (h) CA isozymes, the cytosolic hCA I, hCA II, and hCA VII, the membrane-anchored hCA IV and transmembrane hCA IX. Some of these compounds showed efficient activity (in the nanomolar range) against the cytosolic isoform hCA VII, which is a key CA enzyme involved in brain metabolism. Moderate activity was observed against hCA I and hCA IV (in the nanomolar to low micromolar range). The structure-activity relationship for activation of these isoforms with the new histamine Schiff bases is discussed in detail based on the nature of the aliphatic, aromatic, or heterocyclic moiety present in the aldehyde fragment of the molecule, which may participate in diverse interactions with amino acid residues at the entrance of the active site, where activators bind, and which is the most variable part among the different CA isoforms.
通过组胺（一种著名的碳酸酐酶（CA，E.C 4.2.2.1.）激活剂药效基团）与取代醛反应，合成了一系列20种组胺席夫碱。所得到的组胺席夫碱被作为五种选定的人类（h）CA同工酶的激活剂进行测定，这五种同工酶分别是胞质型hCA I、hCA II和hCA VII，膜锚定型hCA IV和跨膜型hCA IX。其中一些化合物对胞质同工型hCA VII显示出高效活性（在纳摩尔范围内），hCA VII是参与脑代谢的一种关键CA酶。对hCA I和hCA IV观察到中等活性（在纳摩尔到低微摩尔范围内）。基于分子醛片段中存在的脂肪族、芳香族或杂环部分的性质，详细讨论了这些同工型与新的组胺席夫碱激活作用的构效关系，该部分可能与激活剂结合的活性位点入口处的氨基酸残基发生多种相互作用，并且是不同CA同工型中变化最大的部分。
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