A new series of thirty s-triazinyl-substituted aminoalkylbenzenesulfonamides, incorporating a symmetric pair of amino acid moieties, is reported, together with inhibition studies of physiologically relevant human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms. Specifically, against the cytosolic hCA I, II, transmembrane hCA IV and the tumor-associated, membrane-bound hCA IX.

The compounds were prepared by nucleophilic substitution of chlorine atoms from cyanuric chloride (2,4,6-trichloro-1,3,5-triazine) using environmentally friendly water-based synthetic conditions. The products yields ranged in the interval of 43–97%. Purity of the products was verified by the HPLC-DAD-ESI-Q-TOF MS method. Identity of the products was confirmed by the same method plus NMR and IR.

The products showed weak inhibition of the cytosolic, off-target isozyme hCA II, but some of them were low nanomolar (i.e. strong) inhibitors of the tumor-associated hCA IX. The series offered representatives selective towards isozymes hCA I, IV and IX. 2,2′-((6-((4-sulfamoylphenethyl)amino)-1,3,5-triazine-2,4-diyl)bis(imino))disuccinic acid demonstrated highest selectivity to the tumor-associated isoform hCA IX over off-target isozymes, with impressive K_I ratio (hCA II/hCA IX) 213.9 and inhibition constant equal to acetazolamide (K_I = 25.8 nM). Although the selectivities of some other products, e.g. those conjugating Leu and Glu, were a bit lower (188.7 and 84.3, respectively) their inhibition constants were similar to acetazolamide too (24.0 and 27.1, respectively).

The selected most impressive results from the inhibition study were interpreted via molecular modeling experiment (docking in Glide) revealing different inter-molecular enzyme-substrate interaction of 2,2′-((6-((4-sulfamoylphenethyl)amino)-1,3,5-triazine-2,4-diyl)bis(imino))disuccinic acid within specific hCA IX and hCA II microregions. Therefore, several selected compounds from this study can be considered as highly effective and selective inhibitors of hCA IX, worthy to further (preclinical) investigation.

据报道，一系列新的三十个被三-三嗪基取代的氨基烷基苯磺酰胺结合了一个对称的氨基酸部分，并且对生理相关的人类碳酸酐酶（hCA，EC 4.2.1.1）同工型进行了抑制研究。具体而言，针对细胞质hCA I，II，跨膜hCA IV和与肿瘤相关的膜结合hCA IX。

通过使用环境友好的水基合成条件，通过氰尿酰氯（2,4,6-三氯-1,3,5-三嗪）中氯原子的亲核取代来制备化合物。产品收率范围在43–97％之间。产物的纯度通过HPLC-DAD-ESI-Q-TOF MS方法验证。通过相同的方法加上NMR和IR确认产物的身份。

该产品对胞质脱靶同工酶hCA II的抑制作用较弱，但其中一些是与肿瘤相关的hCA IX的低纳摩尔（即强）抑制剂。该系列提供了对同功酶hCA I，IV和IX选择性的代表。2,2'-（（（6-（（4-氨磺酰基苯乙基）氨基）-1,3,5-三嗪-2,4-二基）双（亚氨基））二琥珀酸显示出对肿瘤相关同种型hCA IX的最高选择性脱靶同工酶，具有令人印象深刻的K _I比（hCA II / hCA IX）213.9，抑制常数等于乙酰唑胺（K _I  = 25.8 nM）。尽管某些其他产物（例如与Leu和Glu结合的产物）的选择性较低（分别为188.7和84.3），但它们的抑制常数也与乙酰唑胺相似（分别为24.0和27.1）。

通过分子模拟实验（在Glide中对接）解释了抑制研究中所选的最令人印象深刻的结果，揭示了2,2'-（（6-（（4-氨磺酰基苯乙基）氨基）-1，在特定的hCA IX和hCA II微观区域内的3,5-三嗪-2,4-二基）双（亚氨基）二琥珀酸。因此，从这项研究中选择的几种化合物可以被认为是hCA IX的高效和选择性抑制剂，值得进一步（临床前）研究。