New Sesquiterpene Lactones from Laurus nobilis Leaves as Inhibitors of Nitric Oxide Production

Abstract

Two new metabolites 5αH,7αH-eudesman-4α,6α,11,12-tetraol (1) and 1β,15-dihydroxy-5αH,7αH-eudesma-3,11(13)-dien-12,6α-olide (2) have been isolated from the methanolic extract of Laurus nobilis L. leaves. Their structures were determined through analysis of their one- and two-dimensional NMR spectral data (¹H- and ¹³C-NMR, DEPT, COSY, HMQC, HMBC and ROESY). The relative stereochemistry is proposed on the basis of combined J-based configuration analysis and ROESY data. In addition, three known sesquiterpene lactones santamarine (3), reynosin (4) and costunolide (5) along with blumenol C (6) were isolated and identified by spectral means. The isolated compounds 1 - 6 were found to inhibit nitric oxide (NO) production in lipopolysaccharide (LPS)-activated murine macrophages. The most active compound 2 potently inhibited NO₂ ^- release with an IC₅₀ value of 0.8 μM.

Key words

Laurus nobilis - Lauraceae - sesquiterpenoids - eudesmane - costunolide - nitric oxide

References

• 1 Fiorini C, Fouraste I, David B, Bessiere J M. Composition of the flower, leaf and stem essential oils from L nobilis L.  Flavour Fragr Journal. 1997;  12 91-3
• 2 Tada M, Takeda K. Sesquiterpenes of Lauraceae plants IV. Germacranolides from Laurus nobilis L.  Chem Pharm Bull. 1976;  24 667-71
• 3 El-Feraly F S, Benigni D A. Sesquiterpene lactones of Laurus nobilis leaves.  J Nat Prod. 1980;  43 527-31
• 4 Fischer N H, Lu T, Cantrell C L, Castaneda-Acosta J, Quijano L, Franzblau S G. Antimycobacterial evaluation of germacranolides.  Phytochemistry. 1998;  49 559-64
• 5 Matsuda H, Kagerura T, Toguchida I, Ueda H, Morikawa T, Yoshikawa M. Inhibitory effects of sesquiterpene from bay leaf on nitric oxide production in lipopolysaccharide-activated macrophages: structure requirement and role of heat shock protein induction.  Life Science. 2000;  66 2151-7
• 6 Sun C M, Syu W J, Don M J, Lu J J, Lee G H. Cytotoxic sesquiterpene lactones from the root of Saussurea lappa .  J Nat Prod. 2003;  66 1175-80
• 7 Barrero A F, Oltra J E, Cuerva J M, Rosales A. Effects of solvents and water in Ti(III)-mediated radical cyclization of epoxygermacranolides. Straightforward synthesis and absolute stereochemistry of (+)-3α-hydroxyreynosin and related eudesmanolides.  J Org Chem. 2002;  67 2566-71
• 8 El-Feraly F S, Chan Y M, Capiton G A. Isolation and characterization of peroxycostunolide (verlotorin) and peroxypartenolide from Magnolia grandiflora. Carbon-13 NMR spectroscopy of costunolide and related compounds.  J Org Chem. 1979;  44 3952-3955
• 9 Galbraith M N, Horn D HS. Structures of the natural products blumenol A, B and C. J Chem Soc Chem Commun 1972: 113-4
• 10 Kupchan S M, Britton R W, Ziegler M F, Siegel C W. Bruceantin, a new potent antileukemic simaroubolide from Brucea antidysenterica .  J Org Chem. 1973;  38 178-9
• 11 Denizot F, Lang R. Rapid colorimetric assay for cell growth and survival modifications to the tetrazolium dye procedure giving improved sensitivity and reliability.  J Immunol Meth. 1986;  89 271-7
• 12 Di Rosa M, Radomski M, Carnuccio R, Moncada S. Glucocorticoids inhibit the induction of nitric oxide synthase in macrophages.  Biochem Biophys Res Commun. 1990;  172 1246-52
• 13 Blay G, Cadorna L, Garcia B, Pedro J R. A short synthesis of (+)-colartin and (+)-arbusculin A from (-)-santonin.  J Nat Prod. 1993;  56 1723-7
• 14 Zhu G, Bax A. Measurement of long-range proton-carbon-13 coupling constants from quantitative 2D heteronuclear multiple-quantum correlation spectra.  J Magn Reson. 1993;  104A 353-7
• 15 Murata M, Matsuoka S, Matsumori N, Paul G K, Tachibana K. Absolute configuration of amphidinol 3, the first complete structure determination from amphidinol homologues: application of a new configuration analysis based on carbon-hydrogen spin-coupling constants.  J Am Chem Soc. 1999;  121 870-1
• 16 Matsumori N, Kaneno D, Murata M, Nakamura H, Tachibana K. Stereochemical determination of acyclic structures based on carbon-proton spin-coupling constants. A method of configuration analysis for natural products.  J Org Chem. 1999;  64 866-76
• 17 Appendino G, Tagliapietra S, Nano G M, Cisero M. A sesquiterpene alcohol from the fruits of Laurus nobilis .  Phytochemistry. 1992;  31 2537-8
• 18 Chayen R, Mazur Y, Wyler H, Berman E, Potgieter E, Goldberg S. Urodiolenone from grapefruit juice, a urinary metabolite found in hypertensive subjects.  Phytochemistry. 1988;  27 369-72
• 19 Weisz A, Oguchi S, Cicatiello L, Esumi H. Dual mechanism for the control of inducible-type NO synthase gene expression in macrophages during activation by interferon-gamma and bacterial lipopolysaccharide-transcriptional and post-transcriptional regulation.  J Biol Chem. 1994;  269 8324-33
• 20 Xie Q W, Kashiwabara Y, Nathan C. Role of transcription factor NF-kappa B/rel in induction of nitric oxide synthase.  J Biol Chem. 1994;  269 4705-8
• 21 Ianaro A, O’Donnell C A, Di Rosa M, Liew F Y. A nitric oxide synthase inhibitor reduces inflammation, down-regulates inflammatory cytokines and enhances interleukin-10 production in carrageenin-induced oedema in mice.  Immunology. 1994;  82 370-5
• 22 Ianaro A, Ialenti A, Sautebin L, Di Rosa M. Nitric oxide inhibits neutrophil infiltration in the reverse passive Arthus reaction in rat skin.  Naunyn-Schmiedeberg’s Arch Pharmacol. 1998;  358 489-95
• 23 Dirsch V M, Stuppner H, Ellmerer-Muller E P, Vollmar A M. Structural requirements of sesquiterpene lactones to inhibit LPS-induced nitric oxide synthesis in RAW 264.7 macrophages.  Bioorg Med Chem. 2000;  8 2747-53
• 24 Matsuda H, Toguchida I, Ninomiya K, Kageura T, Morikawa T, Yoshikawa M. Effects of sesquiterpenes and amino acid-sesquiterpene conjugates from the roots of Saussurea lappa on inducible nitric oxide synthase and heat shock protein in lipopolysaccharide-activated macrophages.  Bioorg Med Chem. 2003;  11 709-15