Carbonic anhydrase inhibitors: E7070, a sulfonamide anticancer agent, potently inhibits cytosolic isozymes I and II, and transmembrane, tumor-associated isozyme IX

• Published in: Bioorganic & medicinal chemistry letters Vol. 14; no. 1; pp. 217 - 223
• Main Authors: Abbate, Francesco, Casini, Angela, Owa, Takashi, Scozzafava, Andrea, Supuran, Claudiu T.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 05.01.2004; Elsevier
• Subjects: Animals; Antigens, Neoplasm - metabolism; Antineoplastic agents; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Binding Sites; Biological and medical sciences; Carbonic Anhydrase I - antagonists & inhibitors; Carbonic Anhydrase I - metabolism; Carbonic Anhydrase II - antagonists & inhibitors; Carbonic Anhydrase II - metabolism; Carbonic Anhydrase Inhibitors - pharmacology; Carbonic Anhydrase IX; Carbonic Anhydrases - metabolism; Cattle; Crystallography, X-Ray; Cytosol - drug effects; Cytosol - enzymology; General aspects; Humans; Isoenzymes - antagonists & inhibitors; Isoenzymes - metabolism; Medical sciences; Pharmacology. Drug treatments; Sulfonamides - chemistry; Sulfonamides - pharmacology; Antineoplastic agent; Sulfonamide; Enzyme; Nitrogen heterocycle; Isozyme; Enzyme inhibitor; Lyases; Inhibitor enzyme complex; Crystallography; Biological activity; Chlorine Organic compounds; Benzenic compound; Carbonate dehydratase; Aromatic compound; Indole derivatives; Chemical synthesis; Carbon-oxygen lyases; Hydro-lyases
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2003.09.062

E7070 [ N-(3-chloro-7-indolyl)-1,4-benzenedisulfonamide] is an anticancer drug candidate under clinical development for the treatment of several types of cancers. We prove here that this compound also acts as a potent carbonic anhydrase (CA) inhibitor. Similarly to the clinically used drugs acetazolamide, methazolamide and topiramate, E7070 showed inhibition constants in the range of 15–31 nM against isozymes I, II and IX, being slightly less effective as a CA IV inhibitor ( K i of 65 nM). The X-ray crystal structure of the adduct of hCA II with E7070 revealed unprecedented interactions between the inhibitor and the active site, with three different conformations of the chloroindole fragment of the inhibitor interacting with different amino acid residues/water molecules of the enzyme. A superimposition of these conformations with those of other sulfonamide/sulfamate CA inhibitors indicated that similar regions of the hCA II active site could be involved in the interaction with inhibitors. Graphic