Carbonic anhydrase inhibitors: X-ray crystal structure of a benzenesulfonamide strong CA II and CA IX inhibitor bearing a pentafluorophenylaminothioureido tail in complex with isozyme II.
N-1-(4-Sulfamoylphenyl)-N-4-pentafluorophenyl-thiosemicarbazide was prepared by the reaction of 4-isothiocyanato-benzenesulfonamide with pentafluorophenyl hydrazine, and proved to be an effective inhibitor of several isozymes of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), such as CA I, II, and IX. Against the physiologically relevant isozymes hCA II and hCA IX, the compound showed inhibition constants in the range of 15-19 nM, whereas it was less effective as a hCA I inhibitor (K(I) of 78 nM). The high-resolution X-ray crystal structure of its adduct with hCA II showed the inhibitor to bind within the hydrophobic half of the enzyme active site, making extensive and strong van der Waals contacts with amino acid residues Gln92, Val121, Phe131, Leu198, Thr200, Pro202, in addition to the coordination of the sulfonamide nitrogen to the Zn(II) ion of the active site, and participation of the SO(2)NH(2) group to a network of hydrogen bonds involving residues Thr199 and Glu106. These results are helpful for the design of better CA II or CA IX inhibitors based on the thioureido-benzenesulfonamide motif, with potential applications as anti-glaucoma or anti-cancer drugs.
Di Fiore
Anna
A
Dipartimento di Chimica Biologica-Sezione Biostrutture and Istituto di Biostrutture e Bioimmagini-CNR, University of Naples 'Federico II', via Mezzocannone 16, 80134 Naples, Italy.
De Simone
Giuseppina
G
Menchise
Valeria
V
Pedone
Carlo
C
Casini
Angela
A
Scozzafava
Andrea
A
Supuran
Claudiu T
CT
D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D001665:Binding Sites; D024402:Carbonic Anhydrase II / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071231:Carbonic Anhydrase IX; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D002256:Carbonic Anhydrases / Q000187:drug effects / Q000378:metabolism*; D018360:Crystallography, X-Ray; D005464:Fluorobenzenes / Q000737:chemistry; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010636:Phenols / Q000737:chemistry; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology; D013890:Thiourea / Q000737:chemistry; D000096926:Benzenesulfonamides; D005466:Fluorocarbons
D000596:Amino Acids; D024402:Carbonic Anhydrase II; D000071231:Carbonic Anhydrase IX; D002257:Carbonic Anhydrase Inhibitors; D002256:Carbonic Anhydrases; D005464:Fluorobenzenes; D007527:Isoenzymes; D010636:Phenols; D013449:Sulfonamides; D013890:Thiourea; D000096926:Benzenesulfonamides; C085539:2,3,4,5,6-pentafluorophenol; D005466:Fluorocarbons; C492796:Car9 protein, mouse