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

Dipartimento di Chimica delle Sostanze Naturali, Università degli Studi di Napoli Federico II, Napoli, Italy.
Planta Medica (Impact Factor: 2.15). 09/2005; 71(8):706-10. DOI: 10.1055/s-2005-864191
Source: PubMed


Two new metabolites 5alphaH,7alphaH-eudesman-4alpha,6alpha,11,12-tetraol (1) and 1beta,15-dihydroxy-5alphaH,7alphaH-eudesma-3,11(13)-dien-12,6alpha-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 ((1)H- and (13)C-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 NO (2)(-) release with an IC (50) value of 0.8 microM.

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    • "In accordance with these observations we presume that the analysis of the mechanism by which L-carnosine reduces ROS level and mostly the study of its potential targets could be critical to elucidate how L-carnosine influences HIF-1α as well the mechanism underlying its anti-proliferative effect on colon cancer cells. Further studies will also be needed to assess the possible involvement of PHDs in the HIF-1α degradation and to evaluate the effect on HIF-1α of natural inhibitors of nitric oxide (NO), available from our laboratories, since it has been demonstrated that NO can regulate HIF-1α activation [33]–[34]. "
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    ABSTRACT: In recent years considerable attention has been given to the use of natural substances as anticancer drugs. The natural antioxidant dipeptide L-carnosine belongs to this class of molecules because it has been proved to have a significant anticancer activity both in vitro and in vivo. Previous studies have shown that L-carnosine inhibits the proliferation of human colorectal carcinoma cells by affecting the ATP and Reactive Oxygen Species (ROS) production. In the present study we identified the Hypoxia-Inducible Factor 1α (HIF-1α) as a possible target of L-carnosine in HCT-116 cell line. HIF-1α protein is over-expressed in multiple types of human cancer and is the major cause of resistance to drugs and radiation in solid tumours. Of particular interest are experimental data supporting the concept that generation of ROS provides a redox signal for HIF-1α induction, and it is known that some antioxidants are able to suppress tumorigenesis by inhibiting HIF-1α. In the current study we found that L-carnosine reduces the HIF-1α protein level affecting its stability and decreases the HIF-1 transcriptional activity. In addition, we demonstrated that L-carnosine is involved in ubiquitin-proteasome system promoting HIF-1α degradation. Finally, we compared the antioxidant activity of L-carnosine with that of two synthetic anti-oxidant bis-diaminotriazoles (namely 1 and 2, respectively). Despite these three compounds have the same ability in reducing intracellular ROS, 1 and 2 are more potent scavengers and have no effect on HIF-1α expression and cancer cell proliferation. These findings suggest that an analysis of L-carnosine antioxidant pathway will clarify the mechanism underlying the anti-proliferative effects of this dipeptide on colon cancer cells. However, although the molecular mechanism by which L-carnosine down regulates or inhibits the HIF-1α activity has not been yet elucidated, this ability may be promising in treating hypoxia-related diseases.
    Full-text · Article · May 2014 · PLoS ONE
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    • "Michelia compressa is a common origin of wooden furniture used worldwide. Costunolide has been also identified in several species of plants, including Saussurea lappa C.B. Clarke [2], Aucklandia lappa Decne [3], Laurus nobilis [4], Magnolia grandiflora [5] and Michelia floribunda [6]. Bocca et al reported that costunolide interfered with the microtubule proteins [7]. "
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    ABSTRACT: This work aimed to investigate the effect of costunolide, a sesquiterpene lactone isolated from Michelia compressa, on cell cycle distribution and radiosensitivity of human hepatocellular carcinoma (HCC) cells. The assessment used in this study included: cell viability assay, cell cycle analysis by DNA histogram, expression of phosphorylated histone H3 (Ser 10) by flow cytometer, mitotic index by Liu's stain and morphological observation, mitotic spindle alignment by immunofluorescence of alpha-tubulin, expression of cell cycle-related proteins by Western blotting, and radiation survival by clonogenic assay. Our results show that costunolide reduced the viability of HA22T/VGH cells. It caused a rapid G2/M arrest at 4 hours shown by DNA histogram. The increase in phosphorylated histone H3 (Ser 10)-positive cells and mitotic index indicates costunolide-treated cells are arrested at mitosis, not G2, phase. Immunofluorescence of alpha-tubulin for spindle formation further demonstrated these cells are halted at metaphase. Costunolide up-regulated the expression of phosphorylated Chk2 (Thr 68), phosphorylated Cdc25c (Ser 216), phosphorylated Cdk1 (Tyr 15) and cyclin B1 in HA22T/VGH cells. At optimal condition causing mitotic arrest, costunolide sensitized HA22T/VGH HCC cells to ionizing radiation with sensitizer enhancement ratio up to 1.9. Costunolide could reduce the viability and arrest cell cycling at mitosis in hepatoma cells. Logical exploration of this mitosis-arresting activity for cancer therapeutics shows costunolide enhanced the killing effect of radiotherapy against human HCC cells.
    Full-text · Article · May 2011 · Radiation Oncology
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    • "For the major compound 3, a blumenol C derivative hydroxylated at the enone chromophore, a strong positive Cotton effect ([H] M215 + 14,254) was found indicating an identical configuration. The assignment of the 6R-configuration of blumenol C in blumenin isomers is in accordance with previous blumenol C reports (Aasen et al., 1974; Siddiqui et al., 2003; D'Abrosca et al., 2004; DellaGreca et al., 2004; Park et al., 2004; De Marino et al., 2005). By external standardization (see Section 3) the amount of accumulating cyclohexenone and mycorradicin derivatives in mycorrhizal roots (25 month after inoculation) were determined to be 289.5 nmol and 49.8 nmol per g fr. "
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    ABSTRACT: Colonization of roots of Ornithogalum umbellatum by the arbuscular mycorrhizal fungus Glomus intraradices induced the accumulation of different types of apocarotenoids. In addition to the mycorrhiza-specific occurrence of cyclohexenone derivatives and the "yellow pigment" described earlier, free mycorradicin and numerous mycorradicin derivatives were detected in a complex apocarotenoid mixture for the first time. From the accumulation pattern of the mycorradicin derivatives their possible integration into the continuously accumulating "yellow pigment" is suggested. Structure analyses of the cyclohexenone derivatives by MS and NMR revealed that they are mono-, di- and branched triglycosides of blumenol C, 13-hydroxyblumenol C, and 13-nor-5-carboxy-blumenol C, some of which contain terminal rhamnose as sugar moiety.
    Full-text · Article · Jul 2006 · Phytochemistry
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