Inhibitors of inducible NO synthase expression: total synthesis of (S)-curvularin and its ring homologues.
(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.
Elzner
Stephan
S
Institut für Organische Chemie, Naturstoffsynthese-Zentrum, Universität Mainz, Duesbergweg 10-14, 55128 Mainz, Germany.
Schmidt
Denise
D
Schollmeyer
Dieter
D
Erkel
Gerhard
G
Anke
Timm
T
Kleinert
Hartmut
H
Förstermann
Ulrich
U
Kunz
Horst
H
D002460:Cell Line; D018360:Crystallography, X-Ray; D003500:Cyclization; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects* / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D007783:Lactones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors* / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D013237:Stereoisomerism; D015025:Zearalenone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D004791:Enzyme Inhibitors; D007783:Lactones; D015025:Zearalenone; D052247:Nitric Oxide Synthase Type II; C013455:curvularin