Carbonic anhydrase inhibitors. Inhibition of cytosolic/tumor-associated carbonic anhydrase isozymes I, II, IX, and XII with Schiff's bases incorporating chromone and aromatic sulfonamide moieties, and their zinc complexes.
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.
Puccetti
Luca
L
Ospedale San Lazzaro, Divisione di Urologia, Via Pierino Belli 26, 12051 Alba, Cuneo, Italy.
Fasolis
Giuseppe
G
Vullo
Daniela
D
Chohan
Zahid H
ZH
Scozzafava
Andrea
A
Supuran
Claudiu T
CT
D000951:Antigens, Neoplasm / Q000737:chemistry* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D024401:Carbonic Anhydrase I / Q000737:chemistry* / Q000378:metabolism; D024402:Carbonic Anhydrase II / Q000737:chemistry* / Q000378:metabolism; D000071231:Carbonic Anhydrase IX; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000737:chemistry* / Q000378:metabolism; D002462:Cell Membrane / Q000201:enzymology; D002867:Chromones / Q000138:chemical synthesis / Q000737:chemistry; D003600:Cytosol / Q000201:enzymology*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D015394:Molecular Structure; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000378:metabolism; D012545:Schiff Bases / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry; D017967:Zinc Compounds / Q000138:chemical synthesis / Q000737:chemistry
D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D002257:Carbonic Anhydrase Inhibitors; D002867:Chromones; D007527:Isoenzymes; D009419:Nerve Tissue Proteins; D012545:Schiff Bases; D013449:Sulfonamides; D017967:Zinc Compounds; D024401:Carbonic Anhydrase I; D024402:Carbonic Anhydrase II; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases