Carbonic anhydrase inhibitors. N-cyanomethylsulfonamides--a new zinc binding group in the design of inhibitors targeting cytosolic and membrane-anchored isoforms.
A series of N-cyanomethyl aromatic sulfonamides and bis-sulfonamides was prepared by reaction of arylsulfonyl halides with aminoacetonitrile. The obtained derivatives incorporated various aryl moieties, such as 4-halogeno/alkyl/aryl/nitro-substituted-phenyl, pentafluorophenyl or 2-naphthyl. Moderate inhibitory activity was detected for some compounds against the cytosolic human isoform II of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1), hCA II, with inhibition constants of 90, 180 and 560n M for the 4-nitrophenyl-, 4-iodophenyl- and pentafluorophenyl-N-cyanomethylsulfonamides, respectively. Other derivatives acted as weak inhibitors of isoforms hCA I (KIs of 720 nM-45 microM), hCA II (KIs of 1000-9800 nM) and hCA IX (KIs of 900-10200 nM). Thus, the N-cyanomethylsulfonamide zinc binding group is less effective than the sulfonamide, sulfamate or sulfamide ones for the design of effective CA inhibitors.
Winum
Jean-Yves
JY
Laboratoire de Chimie Biomoléculaire, Université Montpellier II, UMR 5032, Ecole Nationale Supgrieure de Chimie de Montpellier, 8 rue de l'Ecole Normale, Montpellier, France. winumj@univ-montp2.fr
Cecchi
Alessandro
A
Seridi
Achour
A
Scozzafava
Andrea
A
Montero
Jean-Louis
JL
Supuran
Claudiu T
CT
D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D002462:Cell Membrane / Q000201:enzymology*; D003600:Cytosol / Q000201:enzymology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D011485:Protein Binding; D020033:Protein Isoforms; D013449:Sulfonamides / Q000737:chemistry*; D015032:Zinc / Q000737:chemistry*
D002257:Carbonic Anhydrase Inhibitors; D020033:Protein Isoforms; D013449:Sulfonamides; D015032:Zinc