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Inhibitors of Inducible NO Synthase Expression: Total Synthesis of ( S )‐Curvularin and Its Ring Homologues
Author(s) -
Elzner Stephan,
Schmidt Denise,
Schollmeyer Dieter,
Erkel Gerhard,
Anke Timm,
Kleinert Hartmut,
Förstermann Ulrich,
Kunz Horst
Publication year - 2008
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200800022
Subject(s) - reporter gene , chemistry , luciferase , enos , transfection , cytotoxicity , stereochemistry , ring (chemistry) , promoter , biosynthesis , biochemistry , enzyme , microbiology and biotechnology , nitric oxide synthase , gene , gene expression , biology , in vitro , organic chemistry
( S )‐Curvularin and its 13‐, 14‐, and 16‐membered lactone homologues were synthesized through a uniform strategy in which a Kochi oxidative decarboxylation and ring‐closing metathesis reactions constitute the key processes. In the evaluation of the anti‐inflammatory effects of the synthesized compounds in assays using cells stably transfected with a human iNOS promoter–luciferase reporter gene construct, the 14‐ and 16‐membered homologues showed a slightly higher inhibitory effect towards iNOS promoter activity than curvularin itself. However, the larger ring homologues also exhibited higher cytotoxicity, manifest in downregulated eNOS promoter activity. In contrast, the di‐ O ‐acetyl and 4‐chloro derivatives of ( S )‐curvularin showed higher inhibitory efficiency towards induction of the iNOS promoter and less negative effect on eNOS promoter activity than curvularin.