Puccetti Luca, Fasolis Giuseppe, Vullo Daniela, Chohan Zahid H, Scozzafava Andrea, Supuran Claudiu T
Ospedale San Lazzaro, Divisione di Urologia, Via Pierino Belli 26, 12051 Alba, Cuneo, Italy.
Bioorg Med Chem Lett. 2005 Jun 15;15(12):3096-101. doi: 10.1016/j.bmcl.2005.04.055.
A series of Schiff's bases was prepared by reaction of 3-formyl-chromone or 6-methyl-3-formyl-chromone with aromatic sulfonamides, such as sulfanilamide, homosulfanilamide, 4-aminoethyl-benzenesulfonamide, a pyrimidinyl-substituted sulfanilamide derivative, sulfaguanidine and 4-amino-6-trifluoromethyl-benzene-1,3-disulfonamide. The zinc complexes of these sulfonamides have also been obtained. The new derivatives and their Zn(II) complexes were investigated for the inhibition of four physiologically relevant isozymes of carbonic anhydrase (CA, EC 4.2.1.1): the cytosolic isoforms I and II, as well as the tumor-associated, transmembrane isozymes CA IX and XII. Except for the sulfaguanidine-derived compounds which were devoid of activity against all isozymes, the other sulfonamides and their metal complexes showed interesting inhibitory activity. Against isozyme CA I, the inhibition constants were in the range of 13-100 nM, against isozyme CA II in the range of 1.9-102 nM, against isozyme CA IX in the range of 6.3-48nM, and against CA XII in the range of 5.9-50nM. Generally, the formyl-chromone derived compounds were better CA inhibitors as compared to the corresponding 6-methyl-chromone derivatives, and for the simple, benzenesulfonamide derivatives activity increased with an increase of the spacer from sulfanilamide to homosulfanilamide and 4-aminoethylbenzenesulfonamide derivatives, respectively. Some of these compounds may show applications for the development of therapies targeting hypoxic tumors in which CA IX and XII are often highly overexpressed.
通过3-甲酰基色酮或6-甲基-3-甲酰基色酮与芳香族磺酰胺（如磺胺、同型磺胺、4-氨基乙基苯磺酰胺、嘧啶基取代的磺胺衍生物、磺胺脒和4-氨基-6-三氟甲基苯-1,3-二磺酰胺）反应制备了一系列席夫碱。还获得了这些磺酰胺的锌配合物。研究了这些新衍生物及其锌（II）配合物对四种生理相关碳酸酐酶（CA，EC 4.2.1.1）同工酶的抑制作用：胞质同工酶I和II，以及肿瘤相关的跨膜同工酶CA IX和XII。除了对所有同工酶均无活性的磺胺脒衍生化合物外，其他磺酰胺及其金属配合物表现出有趣的抑制活性。对于同工酶CA I，抑制常数范围为13 - 100 nM，对于同工酶CA II为1.9 - 102 nM，对于同工酶CA IX为6.3 - 48 nM，对于CA XII为5.9 - 50 nM。一般来说，与相应的6-甲基色酮衍生物相比，甲酰基色酮衍生的化合物是更好的CA抑制剂，对于简单的苯磺酰胺衍生物，从磺胺到同型磺胺和4-氨基乙基苯磺酰胺衍生物，随着间隔基团的增加活性增强。这些化合物中的一些可能在开发针对低氧肿瘤的疗法中显示出应用前景，其中CA IX和XII通常高度过表达。
