Inhibitors of Inducible NO Synthase Expression: Total Synthesis of (S)‐Curvularin and Its Ring Homologues

Abstract ( 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.