Probing Molecular Interactions between Human Carbonic Anhydrases (hCAs) and a Novel Class of Benzenesulfonamides(386 views) Brunò E, Buemi MR, Di Fiore A, De LucaL, Ferro S, Angeli A, Cirilli R, Sadutto D, Alterio V, Monti SM, Supuran CT, De Simone G, Gitto R
J Med Chem (ISSN: 0022-2623, 1520-4804, 0022-2623print), 2017 May 25; 60(10): 4316-4326.
Dipartimento di Scienze Chimiche, Biologiche, Farmaceutiche ed Ambientali (CHIBIOFARAM), Università degli Studi di Messina, Viale Annunziata, Messina, I-98168, Italy
Istituto di Biostrutture e Bioimmagini-CNR, Via Mezzocannone 16, Napoli, I-80134, Italy
Dipartimento NEUROFARBA, Università di Firenze, Via Ugo Schiff 6, Sesto Fiorentino, I-50019, Italy
Centro Nazionale Per il Controllo e la Valutazione Dei Farmaci, Istituto Superiore di Sanità, V.le Regina Elena 299, Roma, I-00161, Italy
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Probing Molecular Interactions between Human Carbonic Anhydrases (hCAs) and a Novel Class of Benzenesulfonamides
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
(K
i
= 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.
Probing Molecular Interactions between Human Carbonic Anhydrases (hCAs) and a Novel Class of Benzenesulfonamides
No results.
Probing Molecular Interactions between Human Carbonic Anhydrases (hCAs) and a Novel Class of Benzenesulfonamides