Total Synthesis of a NoricumazoleA Library and Evaluation of HCV Inhibition

The total synthesis of 16 new ion channel inhibitors derived from noricumazoleA, a secondary metabolite from the myxobacterium Sorangium cellulosum, is reported. Particular focus of library design is put on stereochemical permutations in the central region (C9 and C11), the oxazole moiety and the si...

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Published inChemistry : a European journal Vol. 18; no. 29; pp. 9083 - 9090
Main Authors Barbier, Jenny, Wegner, Jens, Benson, Stefan, Gentzsch, Juliane, Pietschmann, Thomas, Kirschning, Andreas
Format Journal Article
LanguageEnglish
Published Weinheim Wiley Subscription Services, Inc 16.07.2012
Subjects
Analogue
Chemistry
Derivatives
Design engineering
Inhibitors
Ion channels
Libraries
Synthesis
Viruses
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Summary:The total synthesis of 16 new ion channel inhibitors derived from noricumazoleA, a secondary metabolite from the myxobacterium Sorangium cellulosum, is reported. Particular focus of library design is put on stereochemical permutations in the central region (C9 and C11), the oxazole moiety and the side chain at C4 of the isochromanone moiety. NoricumazoleA and all new noricumazole derivatives were tested in an assay system with inhibitory effect on the hepatitisC virus (HCV) life cycle. Most of them are moderate to strong HCV inhibitors (350nM-6nM) but also exert pronounced cytotoxicity. In contrast, the thiazole analogue of noricumazoleA is a strong HCV inhibitor with only moderate cytotoxic property. It may become a lead structure with a good therapeutic index (CC50/IC50) of greater than 10.
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ISSN:0947-6539
1521-3765
DOI:10.1002/chem.201104042