jm7b00264_si_002.csv (0.68 kB)
Probing Molecular Interactions between Human Carbonic Anhydrases (hCAs) and a Novel Class of Benzenesulfonamides
datasetposted on 2017-04-28, 00:00 authored by Elvira Bruno, Maria Rosa Buemi, Anna Di Fiore, Laura De Luca, Stefania Ferro, Andrea Angeli, Roberto Cirilli, Daniele Sadutto, Vincenzo Alterio, Simona Maria Monti, Claudiu T. Supuran, Giuseppina De Simone, Rosaria Gitto
On the basis of X-ray crystallographic studies of the complex of hCA II with 4-(3,4-dihydro-1H-isoquinoline-2-carbonyl)benzenesulfonamide (3) (PDB code 4Z1J), a novel series of 4-(1-aryl-3,4-dihydro-1H-isoquinolin-2-carbonyl)benzenesulfonamides (23–33) was designed. Specifically, our idea was to improve the selectivity toward druggable isoforms through the introduction of additional hydrophobic/hydrophilic functionalities. Among the synthesized and tested compounds, the (R,S)-4-(6,7-dihydroxy-1-phenyl-3,4-tetrahydroisoquinoline-1H-2-carbonyl)benzenesulfonamide (30) exhibited a remarkable inhibition for the brain-expressed hCA VII (Ki = 0.20 nM) and selectivity over wider distributed hCA I and hCA II isoforms. By enantioselective HPLC, we solved the racemic mixture and ascertained that the two enantiomers (30a and 30b) are equiactive inhibitors for hCA VII. Crystallographic and docking studies revealed the main interactions of these inhibitors into the carbonic anhydrase (CA) catalytic site, thus highlighting the relevant role of nonpolar contacts for this class of hCA inhibitors.
isoquinolin -2-carbonylHuman Carbonic AnhydrasesPDB code 4 Z 1JMolecular Interactionsenantioselective HPLCdocking studieshCA inhibitorsnovel seriesNovel Classbrain-expressed hCA VIIracemic mixturehCA VIIK i30 bcarbonic anhydrasehCA II isoforms0.20 nMisoquinoline -2-carbonyldruggable isoformsnonpolar contactsequiactive inhibitorshCA II