o-Benzenedisulfonimido-sulfonamides are potent inhibitors of the tumor-associated carbonic anhydrase isoforms CA IX and CA XII.
By using phthalimido-substituted aromatic sufonamides as lead molecules, a series of new sulfonamides incorporating ortho-benzenedisulfonimide moieties have been synthesized and tested against the human (h) cytosolic carbonic anhydrase (CA, EC 4.2.1.1) isozymes hCA I and hCA II and the transmembrane, tumor-associated isozymes hCA IX and hCA XII. All these compounds showed Ki values lower than 100nM and many of them showed better Kis than the reference compound acetazolamide, a clinically used sulfonamide. The tumor-associated isozymes were better inhibited than the cytosolic ones. A molecular docking within the active site of some CA isoforms, such as hCA I, explained these findings, as the benzenedisulfonimide moiety makes favorable interactions (hydrogen bonds) with amino acid residues involved in binding of inhibitors, such as Gln92, His67, and His64.
Istanbul University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 34116 Beyazıt, Istanbul, Turkey.
Özlen
Ö
Güzel-Akdemir
Atilla
A
Akdemir
Semra
S
Isik
Daniela
D
Vullo
Claudiu T
CT
Supuran
D000086:Acetazolamide / Q000737:chemistry / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D000071231:Carbonic Anhydrase IX; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D002256:Carbonic Anhydrases / Q000737:chemistry* / Q000378:metabolism; D020134:Catalytic Domain; D006801:Humans; D007094:Imides / Q000737:chemistry*; D007700:Kinetics; D062105:Molecular Docking Simulation; D011485:Protein Binding; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism
D000951:Antigens, Neoplasm; D002257:Carbonic Anhydrase Inhibitors; D007094:Imides; D013449:Sulfonamides; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases; C477378:carbonic anhydrase XII; D000086:Acetazolamide