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Carbonic Anhydrase Inhibitors: Synthesis and Inhibition of Cytosolic/Membrane-Associated Carbonic Anhydrase Isozymes I, II, and IX with Sulfonamides Incorporating Hydrazino Moieties

2004; American Chemical Society; Volume: 48; Issue: 6 Linguagem: Inglês

10.1021/jm0494826

1520-4804

Jean‐Yves Winum, Jean-Michel Dogné, Angela Casini, Xavier de Leval, Jean‐Louis Montero, Andrea Scozzafava, Daniela Vullo, Alessio Innocenti, Claudiu T. Supuran,

Chemical Reactions and Mechanisms

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.