Novel sulfonamides incorporating 1,3,5-triazine and amino acid structural motifs as inhibitors of the physiological carbonic anhydrase isozymes I, II and IV and tumor-associated isozyme IX.Bioorg Chem. 2018 12; 81:241-252.BC
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 126.96.36.199) 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 KI ratio (hCA II/hCA IX) 213.9 and inhibition constant equal to acetazolamide (KI = 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.