TY - JOUR
T1 - Probing Molecular Interactions between Human Carbonic Anhydrases (hCAs) and a Novel Class of Benzenesulfonamides
AU - Bruno, Elvira
AU - Buemi, Maria Rosa
AU - Di Fiore, Anna
AU - De Luca, Laura
AU - Ferro, Stefania
AU - Angeli, Andrea
AU - Cirilli, Roberto
AU - Sadutto, Daniele
AU - Alterio, Vincenzo
AU - Monti, Simona Maria
AU - Supuran, Claudiu T.
AU - De Simone, Giuseppina
AU - Gitto, Rosaria
PY - 2017/5/25
Y1 - 2017/5/25
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.jmedchem.7b00264
DO - 10.1021/acs.jmedchem.7b00264
M3 - Article
C2 - 28453941
AN - SCOPUS:85019659841
VL - 60
SP - 4316
EP - 4326
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 10
ER -