Carbonic anhydrase inhibitors: synthesis and inhibition of cytosolic/membrane-associated carbonic anhydrase isozymes I, II, and IX with sulfonamides incorporating hydrazino moieties.
Targeting proteins overexpressed in hypoxic tumors is as an important means of controlling cancer disease. One such protein is the carbonic anhydrase (CA) isoenzyme IX, which in some types of tumors is overexpressed 150-200-fold. We report here a series of sulfonamide derivatives, prepared from 2-carbohydrazido- and 4-carbohydrazido-benzenesulfonamides, which were further derivatized by reaction with aryl isocyanates or arylsulfonyl isocyanates. Several low nanomolar CA IX inhibitors were detected in this way. SAR is discussed for the diverse types of inhibitors and their affinity for different isozymes, with the aim of obtaining isozyme-specific CA IX inhibitors, with putative applications as antitumor drugs.
Winum
Jean-Yves
JY
Polo Scientifico, Laboratorio di Chimica Bioinorganica, Università degli Studi di Firenze, Room 188, Via della Lastruccia 3, 50019 Sesto Fiorentino (Florence), Italy.
Dogné
Jean-Michel
JM
Casini
Angela
A
de Leval
Xavier
X
Montero
Jean-Louis
JL
Scozzafava
Andrea
A
Vullo
Daniela
D
Innocenti
Alessio
A
Supuran
Claudiu T
CT
D000951:Antigens, Neoplasm / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry; D024401:Carbonic Anhydrase I / Q000737:chemistry*; D024402:Carbonic Anhydrase II / Q000737:chemistry*; D000071231:Carbonic Anhydrase IX; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D002256:Carbonic Anhydrases / Q000737:chemistry*; D002462:Cell Membrane / Q000737:chemistry; D003600:Cytosol / Q000737:chemistry; D006834:Hydrazines / Q000737:chemistry; D017953:Isocyanates / Q000138:chemical synthesis / Q000737:chemistry; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry
D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D002257:Carbonic Anhydrase Inhibitors; D006834:Hydrazines; D017953:Isocyanates; D007527:Isoenzymes; D013449:Sulfonamides; D024401:Carbonic Anhydrase I; D024402:Carbonic Anhydrase II; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases