Probing Molecular Interactions between Human Carbonic Anhydrases (hCAs) and a Novel Class of Benzenesulfonamides (657 views)
J Med Chem (ISSN: 0022-2623, 1520-4804, 0022-2623print), 2017 May 25; 60(10): 4316-4326.
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Paper type: Journal Article, Journal Paper,
Impact factor: 6.253, 5-year impact factor: 5.9
Url: doi: 10.1021/acs.jmedchem.7b00264
Keywords: 4 (1 Phenyl 6 Propoxy 3, 4 Dihydro 1h Isoquinoline 2 Carbonyl)benzenesulfonamide, 4 (6 Hydroxy 1 Phenyl 3, 4 (6 Methoxy 1 Phenyl 3, 7 Dihydroxy 1 Phenyl 3, 7 Dimethoxy 1 Phenyl 3, 4 [1 (4 Bromophenyl) 6, 4 Dihydro 1h Isoquinoline 2 Carbonyl]benzenesulfonamide, 4 [1 (4 Chlorophenyl) 6, 4 Dihydro 1h Isoquinoline 2 Carbonyl]benzesulfonamide, 4 [1 (4 Fluorophenyl) 6, 7 Dihydroxy 1 (4 Fluorophenyl) 3, Benzenesulfonamide Derivative, Carbonate Dehydratase Inhibitor, Unclassified Drug, Isoprotein, Isoquinoline Derivative, Article, Drug Design, Drug Structure, Drug Synthesis, Elemental Analysis, Enantiomer, Enantioselectivity, Enzyme Active Site, High Performance Liquid Chromatography, Human, Hydrogen Bond, Molecular Docking, Molecular Interaction, Molecular Model, Proton Nuclear Magnetic Resonance, Racemic Mixture, X Ray Crystallography, Chemistry, Metabolism, Structure Activity Relation, Carbonic Anhydrase Inhibitors, X-Ray, Molecular Docking Simulation, Protein Isoforms, Structure-Activity Relationship,
Affiliations:
*** IBB - CNR ***
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
References:
Not available.
J Med Chem (ISSN: 0022-2623, 1520-4804, 0022-2623print), 2017 May 25; 60(10): 4316-4326.
Export to BibTeX Export to EndNote
Paper type: Journal Article, Journal Paper,
Impact factor: 6.253, 5-year impact factor: 5.9
Url: doi: 10.1021/acs.jmedchem.7b00264
Keywords: 4 (1 Phenyl 6 Propoxy 3, 4 Dihydro 1h Isoquinoline 2 Carbonyl)benzenesulfonamide, 4 (6 Hydroxy 1 Phenyl 3, 4 (6 Methoxy 1 Phenyl 3, 7 Dihydroxy 1 Phenyl 3, 7 Dimethoxy 1 Phenyl 3, 4 [1 (4 Bromophenyl) 6, 4 Dihydro 1h Isoquinoline 2 Carbonyl]benzenesulfonamide, 4 [1 (4 Chlorophenyl) 6, 4 Dihydro 1h Isoquinoline 2 Carbonyl]benzesulfonamide, 4 [1 (4 Fluorophenyl) 6, 7 Dihydroxy 1 (4 Fluorophenyl) 3, Benzenesulfonamide Derivative, Carbonate Dehydratase Inhibitor, Unclassified Drug, Isoprotein, Isoquinoline Derivative, Article, Drug Design, Drug Structure, Drug Synthesis, Elemental Analysis, Enantiomer, Enantioselectivity, Enzyme Active Site, High Performance Liquid Chromatography, Human, Hydrogen Bond, Molecular Docking, Molecular Interaction, Molecular Model, Proton Nuclear Magnetic Resonance, Racemic Mixture, X Ray Crystallography, Chemistry, Metabolism, Structure Activity Relation, Carbonic Anhydrase Inhibitors, X-Ray, Molecular Docking Simulation, Protein Isoforms, Structure-Activity Relationship,
Affiliations:
*** IBB - CNR ***
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
References:
Not available.
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.
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
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