Discovery of novel non-cyclam polynitrogenated CXCR4 coreceptor inhibitors.
作者： Sofia Pettersson , Violeta I. Pérez-Nueno , Laia Ros-Blanco , Raimon Puig de La Bellacasa , María Obdulia Rabal
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摘要: 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 two cyclam moieties are tethered by a 1,4-phenylenebis-(methylene) bridge. It withdrawn from clinical trials owing its lack of oral bioavailability cardiotoxicity. We designed combinatorial library non-cyclam polynitrogenated preserving main features AMD3100. At least nitrogen atoms on each side p-phenylene moiety, one benzylic position other(s) heterocyclic system maintained, distances between them similar atom cyclam. A selection diverse this prepared, their vitro activity tested cultures strains. This led identification novel CXCR4 coreceptor inhibitors without cytotoxicity at concentrations.
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