Magnesium Chelating 2-Hydroxyisoquinolin ...
Document type :
Article dans une revue scientifique: Article original
DOI :
Permalink :
Title :
Magnesium Chelating 2-Hydroxyisoquinoline-1,3(2H,4H)-diones, as Inhibitors of HIV-1 Integrase and/or the HIV-1 Reverse Transcriptase Ribonuclease H Domain: Discovery of a Novel Selective Inhibitor of the Ribonuclease H Function
Author(s) :
Billamboz, Muriel [Auteur]
Chimie Moléculaire et Formulation - EA 4478 [CMF]
Bailly, Fabrice [Auteur]
Chimie Moléculaire et Formulation - EA 4478 [CMF]
Lion, Cédric [Auteur]
Chimie Moléculaire et Formulation - EA 4478 [CMF]
Touati, Nadia [Auteur]
Laboratoire de Chimie Organique et Macromoleculaire [UMR CNRS 8009]
Vezin, Herve [Auteur]
Laboratoire de Chimie Organique et Macromoleculaire [UMR CNRS 8009]
Calmels, Christina [Auteur]
Andréola, Marie-Line [Auteur]
Christ, Frauke [Auteur]
Debyser, Zeger [Auteur]
Cotelle, Philippe [Auteur]
Chimie Moléculaire et Formulation - EA 4478 [CMF]

Chimie Moléculaire et Formulation - EA 4478 [CMF]
Bailly, Fabrice [Auteur]

Chimie Moléculaire et Formulation - EA 4478 [CMF]
Lion, Cédric [Auteur]

Chimie Moléculaire et Formulation - EA 4478 [CMF]
Touati, Nadia [Auteur]
Laboratoire de Chimie Organique et Macromoleculaire [UMR CNRS 8009]
Vezin, Herve [Auteur]

Laboratoire de Chimie Organique et Macromoleculaire [UMR CNRS 8009]
Calmels, Christina [Auteur]
Andréola, Marie-Line [Auteur]
Christ, Frauke [Auteur]
Debyser, Zeger [Auteur]
Cotelle, Philippe [Auteur]

Chimie Moléculaire et Formulation - EA 4478 [CMF]
Journal title :
Journal of Medicinal Chemistry
Abbreviated title :
J. Med. Chem.
Volume number :
54
Pages :
1812-1824
Publisher :
American Chemical Society (ACS)
Publication date :
2011-03-24
ISSN :
0022-2623
English keyword(s) :
Peptides and proteins
Ligands
Inhibitors
Magnesium
Transition metals
Ligands
Inhibitors
Magnesium
Transition metals
HAL domain(s) :
Chimie/Chimie théorique et/ou physique
English abstract : [en]
2-Hydroxyisoquinoline-1,3(2H,4H)-dione was recently discovered as a scaffold for the inhibition of HIV-1 integrase and the ribonuclease H function of HIV-1 reverse transcriptase. First, we investigate its interaction with ...
Show more >2-Hydroxyisoquinoline-1,3(2H,4H)-dione was recently discovered as a scaffold for the inhibition of HIV-1 integrase and the ribonuclease H function of HIV-1 reverse transcriptase. First, we investigate its interaction with Mg2+ and Mn2+ using different spectroscopic techniques and report that 2-hydroxyisoquinoline-1,3(2H,4H)-dione forms a 1:1 complex with Mg2+ but a 1:2 complex with Mn2+. The complex formation requires enolization of the ligand. ESR spectroscopy shows a redox reaction between the ligand and Mn2+ producing superoxide anions. Second, 2-hydroxyisoquinoline-1,3(2H,4H)-dione, its magnesium complex, and its 4-methyl and 2-hydroxy-4-methoxycarbonylisoquinoline-1,3(2H,4H)-diones were tested as inhibitors of HIV-1 integrase, reverse transcriptase ribonuclease H, and DNA polymerase functions. Their antiviral activities were evaluated and 2-hydroxy-4-methoxycarbonyl-isoquinoline-1,3(2H,4H)-dione was found to inhibit the viral replication of HIV-1 in MT-4 cells. Cross-resistance was measured for this compound on three different viral strains. Experimental data suggest that the antiviral activity of 2-hydroxy-4-methoxycarbonylisoquinoline-1,3(2H,4H)-dione is probably due to the RNase H inhibition.Show less >
Show more >2-Hydroxyisoquinoline-1,3(2H,4H)-dione was recently discovered as a scaffold for the inhibition of HIV-1 integrase and the ribonuclease H function of HIV-1 reverse transcriptase. First, we investigate its interaction with Mg2+ and Mn2+ using different spectroscopic techniques and report that 2-hydroxyisoquinoline-1,3(2H,4H)-dione forms a 1:1 complex with Mg2+ but a 1:2 complex with Mn2+. The complex formation requires enolization of the ligand. ESR spectroscopy shows a redox reaction between the ligand and Mn2+ producing superoxide anions. Second, 2-hydroxyisoquinoline-1,3(2H,4H)-dione, its magnesium complex, and its 4-methyl and 2-hydroxy-4-methoxycarbonylisoquinoline-1,3(2H,4H)-diones were tested as inhibitors of HIV-1 integrase, reverse transcriptase ribonuclease H, and DNA polymerase functions. Their antiviral activities were evaluated and 2-hydroxy-4-methoxycarbonyl-isoquinoline-1,3(2H,4H)-dione was found to inhibit the viral replication of HIV-1 in MT-4 cells. Cross-resistance was measured for this compound on three different viral strains. Experimental data suggest that the antiviral activity of 2-hydroxy-4-methoxycarbonylisoquinoline-1,3(2H,4H)-dione is probably due to the RNase H inhibition.Show less >
Language :
Anglais
Audience :
Internationale
Popular science :
Non
Administrative institution(s) :
Université de Lille
CNRS
CNRS
Collections :
Submission date :
2021-06-18T08:07:31Z
2021-10-08T11:41:08Z
2021-10-08T11:41:08Z