TY - JOUR
T1 - Discovery of novel non-cyclam polynitrogenated CXCR4 coreceptor inhibitors
AU - Pettersson, Sofia
AU - Pérez-Nueno, Violeta I.
AU - Ros-Blanco, Laia
AU - De La Bellacasa, Raimon Puig
AU - Rabal, María Obdulia
AU - Batllori, Xavier
AU - Clotet, Bonaventura
AU - Clotet-Codina, Imma
AU - Armand-Ugón, Mercedes
AU - Esté, José
AU - Borrell, José I.
AU - Teixidó, Jordi
PY - 2008/10/20
Y1 - 2008/10/20
N2 - HIV cell fusion and entry have been validated as targets for therapeutic intervention against infection. Bicyclams were the first low-molecular-weight compounds to show specific interaction with CXCR4. The most potent bicyclam was AMD3100, in which the two cyclam moieties are tethered by a 1,4-phenylenebis- (methylene) bridge. It was withdrawn from clinical trials owing to its lack of oral bioavailability and cardiotoxicity. We have designed a combinatorial library of non-cyclam polynitrogenated compounds by preserving the main features of AMD3100. At least two nitrogen atoms on each side of the p-phenylene moiety, one in the benzylic position and the other(s) in the heterocyclic system were maintained, and the distances between them were similar to the nitrogen atom distances in cyclam. A selection of diverse compounds from this library were prepared, and their in vitro activity was tested in cell cultures against HIV strains. This led to the identification of novel potent CXCR4 coreceptor inhibitors without cytotoxicity at the tested concentrations.
AB - HIV cell fusion and entry have been validated as targets for therapeutic intervention against infection. Bicyclams were the first low-molecular-weight compounds to show specific interaction with CXCR4. The most potent bicyclam was AMD3100, in which the two cyclam moieties are tethered by a 1,4-phenylenebis- (methylene) bridge. It was withdrawn from clinical trials owing to its lack of oral bioavailability and cardiotoxicity. We have designed a combinatorial library of non-cyclam polynitrogenated compounds by preserving the main features of AMD3100. At least two nitrogen atoms on each side of the p-phenylene moiety, one in the benzylic position and the other(s) in the heterocyclic system were maintained, and the distances between them were similar to the nitrogen atom distances in cyclam. A selection of diverse compounds from this library were prepared, and their in vitro activity was tested in cell cultures against HIV strains. This led to the identification of novel potent CXCR4 coreceptor inhibitors without cytotoxicity at the tested concentrations.
KW - Antiviral agents
KW - Heterocycles
KW - Medicinal chemistry
KW - Molecular modeling
KW - Reductive amination
UR - http://www.scopus.com/inward/record.url?scp=54849425551&partnerID=8YFLogxK
U2 - 10.1002/cmdc.200800145
DO - 10.1002/cmdc.200800145
M3 - Article
C2 - 18671217
AN - SCOPUS:54849425551
SN - 1860-7179
VL - 3
SP - 1549
EP - 1557
JO - ChemMedChem
JF - ChemMedChem
IS - 10
ER -