COX-2 inhibitory activity of homoisoflavanones and xanthones from the bulbs of the Southern African Ledebouria socialis and Ledebouria ovatifolia (Hyacinthaceae: Hyacinthoideae)

Waller, Catherine; Thumser, Alfred E.; Langat, Moses K.; Crouch, Neil R.; Mulholland, Dulcie A.

doi:10.1016/j.phytochem.2013.06.024

Cited by 38 publications

(38 citation statements)

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“…on COX-2 expression and activity is consistent with these findings and those of Waller et al 5 who reported that homoisoflavones from Ledebouria socialis and L. ovatifolia inhibited COX-2 activity based on an in vitro assay. However, the findings of the present study suggest that in terms of their therapeutic potential, with regard to CRC cells, the target may be COX-2 activity rather than its expression.…”

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confidence: 92%

Phytochemical Investigations of Three Rhodocodon (Hyacinthaceae Sensu APG II) Species

et al. 2017

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The genus Rhodocodon (Hyacinthaceae sensu APG II) is endemic to Madagascar and its phytochemistry has not been described previously. The phytochemistry of three species in this genus has been investigated and eight compounds, including three bufadienolides (compounds 1, 4, and 5), a norlignan (2), and four homoisoflavonoids (compounds 3 and 6-8) have been isolated and identified. Compounds 1-3 and 6-8 have not been described previously. The COX-2 inhibitory activity of compound 6 and compound 7 acetate (compound 7A) were investigated on isolated colorectal cancer cells. Compounds 6 and 7A inhibited COX-2 by 10% and 8%, respectively, at a concentration of 12.5 M compared to 12% for 1 mM aspirin (the positive control).

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confidence: 92%

Phytochemical Investigations of Three Rhodocodon (Hyacinthaceae Sensu APG II) Species

et al. 2017

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“…Natural small molecules remain promising drug sources (12,13). In the present study, we report that a natural small-molecule probe, sappanone A (SA, Fig.1A), demonstrated significant inhibitory effects on neuroinflammation by directly targeting the conserved cysteine residue 140 (Cys140) in the noncatalytic Bateman domain of IMPDH2.…”

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confidence: 80%

Highly selective inhibition of IMPDH2 provides the basis of antineuroinflammation therapy

Liao

Song

Wang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Inosine monophosphate dehydrogenase (IMPDH) of human is an attractive target for immunosuppressive agents. Currently, smallmolecule inhibitors do not show good selectivity for different IMPDH isoforms (IMPDH1 and IMPDH2), resulting in some adverse effects, which limit their use. Herein, we used a small-molecule probe specifically targeting IMPDH2 and identified Cysteine residue 140 (Cys140) as a selective druggable site. On covalently binding to Cys140, the probe exerts an allosteric regulation to block the catalytic pocket of IMPDH2 and further induces IMPDH2 inactivation, leading to an effective suppression of neuroinflammatory responses. However, the probe does not covalently bind to IMPDH1. Taken together, our study shows Cys140 as a druggable site for selectively inhibiting IMPDH2, which provides great potential for development of therapy agents for autoimmune and neuroinflammatory diseases with less unfavorable tolerability profile.nosine monophosphate dehydrogenase (IMPDH) is a major rate-limiting enzyme involved in guanosine and deoxyguanosine biosynthesis and widely expressed in immunocytes (1). There exist two IMPDH isoforms (IMPDH1 and IMPDH2), which are encoded by distinct genes (2, 3). Many inflammation-relevant diseases have been specially characterized by the high expression of isoform II of IMPDH (IMPDH2) in rapidly proliferating immunocytes, rather than the "housekeeping" type I isoform (IMPDH1) in normal human leukocytes and lymphocytes (4, 5). Therefore, selective targeting of IMPDH2 with small molecules is an attractive topic for development of antiinflammation agents with low side effects.Both IMPDH isoforms contain two major domains: the catalytic domain for substrate interaction and the Bateman domain, which is not required for catalytic activity but exerts an important allosteric regulation effect on IMPDH activity by communicating with the catalytic domain (6, 7). By influencing catalytic domain activity, the Bateman domain can regulate IMPDH function and further blocks the downstream-of-inflammation signaling pathways (8, 9). Currently, IMPDH inhibitors are divided into two major categories. One kind of inhibitor, including 6-chloropurine riboside ribavirin and mizoribine, targets the binding pocket of the natural substrate, inosine monophosphate (IMP). Another kind of inhibitor (e.g., mycophenolic acid and thiazole-4-carboxamide adenine dinucleotide) targets the site of the cofactor, NAD + / NADH, which usually leads to low selectivity or even side effects in clinical trials, such as diarrhea and leukopenia (10, 11). Moreover, a third ligand has been speculated to bind to a possible site far from the IMP and NAD + pockets as an allosteric inhibitor. However, an allosteric site for designing selective IMPDH2 inhibitors has been largely unexplored.Natural small molecules remain promising drug sources (12, 13). In the present study, we report that a natural small-molecule probe, sappanone A (SA, Fig.1A), demonstrated significant inhibitory effects on neuroinflammation by directly targetin...

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“…From this study, we can also state that norathyriol 4a showed a similar inhibition of COX-1 and COX-2 activities and a higher efficiency to inhibit human recombinant 5-LOX [26]. The inhibition of ram seminal vesicle COX-1 activity was also examined for furanochromone 5 [29] and trihydroxylated xanthone 6, isolated from the bulbs of Ledebouria ovatifolia [33] (Fig. 4).…”

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confidence: 57%

2,3-Diarylxanthones as Potential Inhibitors of Arachidonic Acid Metabolic Pathways

et al. 2017

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Abstract-In response to an inflammatory stimulus, arachidonic acid (AA), the main polyunsaturated fatty acid present in the phospholipid layer of cell membranes, is released and metabolized to a series of eicosanoids. These bioactive lipid mediators of inflammation arise physiologically through the action of the enzymes 5-lipoxygenase (5-LOX) and cyclooxygenases (constitutive COX-1 and inducible COX-2). It is believed that dual inhibition of 5-LOX and COXs may have a higher beneficial impact in the treatment of inflammatory disorders rather than the inhibition of each enzyme. With this demand for new dual-acting antiinflammatory agents, a range of 2,3-diarylxanthones were tested through their ability to interact in the AA metabolism. In vitro anti-inflammatory activity was evaluated through the inhibition of 5-LOX-catalyzed leukotriene B 4 (LTB 4 ) formation in human neutrophils and inhibition of COX-1-and COX-2-catalyzed prostaglandin E 2 (PGE 2 ) formation in human whole blood. The results showed that some of the studied arylxanthones were able to prevent LTB 4 production in human neutrophils, in a concentration-dependent manner. The xanthone with a 2-catechol was the most active one (IC 50 ∼ 9 μM). The more effective arylxanthones in preventing COX-1-catalyzed PGE 2 production presented IC 50 values from 1 to 7 μM, exhibiting a structural feature with at least one non-substituted aryl group. All the studied arylxanthones were ineffective to prevent the formation of PGE 2 catalyzed by COX-2, up to the maximum concentration of 100 μM. The ability of the tested 2,3-diarylxanthones to interact with both 5-LOX and COX-1 pathways constitutes an important step in the research of novel dual-acting anti-inflammatory drugs.

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COX-2 inhibitory activity of homoisoflavanones and xanthones from the bulbs of the Southern African Ledebouria socialis and Ledebouria ovatifolia (Hyacinthaceae: Hyacinthoideae)

Cited by 38 publications

References 35 publications

Phytochemical Investigations of Three Rhodocodon (Hyacinthaceae Sensu APG II) Species

Phytochemical Investigations of Three Rhodocodon (Hyacinthaceae Sensu APG II) Species

Highly selective inhibition of IMPDH2 provides the basis of antineuroinflammation therapy

2,3-Diarylxanthones as Potential Inhibitors of Arachidonic Acid Metabolic Pathways

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