New Brominated and Halogen-less Derivatives and Structure-activity Relationship of Azaphilones Inhibiting gp120-CD4 Binding.

Matsuzaki, Keiichi; Tahara, Harumi; Inokoshi, Junji; Tanaka, Haruo; Masuma, Rokuro; Ōmura, Satoshi

doi:10.7164/antibiotics.51.1004

Cited by 81 publications

(72 citation statements)

References 16 publications

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“…2,3) Although previous publications showed that azaphilones exhibit broad activities in many biological systems, such as cholesteryl ester transfer protein, 4) monoamine oxidase inhibition, 5) endothelin receptor binding, 6) the inhibition of gp120-CD4 binding, 7) telomerase inhibition, 8) the induction of Epstein-Barr virus, 9) and antimicrobial activities, 3,10,11) there is no report about the inhibition of nitric oxide (NO) production by azaphilones.…”

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Inhibition of Nitric Oxide Production in RAW 264.7 Cells by Azaphilones from Xylariaceous Fungi

Quang

Harinantenaina

Nishizawa

et al. 2006

Biological & Pharmaceutical Bulletin

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The Xylariaceae (Ascomycete) is a large family and currently comprises more than 36 genera. So far, at least one third of these genera have been chemically investigated. 1)One of these specific metabolites repeatedly isolated from this family is azaphilone, with various substitution groups linked to the main skeleton.2,3) Although previous publications showed that azaphilones exhibit broad activities in many biological systems, such as cholesteryl ester transfer protein, 4) monoamine oxidase inhibition, 5) endothelin receptor binding, 6) the inhibition of gp120-CD4 binding, 7) telomerase inhibition, 8) the induction of Epstein-Barr virus, 9) and antimicrobial activities, 3,10,11) there is no report about the inhibition of nitric oxide (NO) production by azaphilones.NO is synthesized from L-arginine by nitric oxide synthase (NOS). Currently, three distinct isoforms of NOS have been identified: Neuronal NOS (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS).12) Of these, iNOS is an important enzyme involved in the regulation of inflammation 13) and in the generation of a large amount of NO.14) Overproduction of NO by iNOS has been implicated in various pathological processes including septic shock, tissue damage following inflammation, and rheumatoid arthritis. [15][16][17][18][19] Therefore, suppression of nitric oxide (NO) production in macrophages could be a target for potential anti-inflammatory drugs.In the present study, we screened the inhibitory activity of fifteen azaphilones, which were isolated from mushrooms belonging to the Xylariaceae family, and also elucidated the mechanism of inhibition of NO production stimulated by lipopolysaccharide (LPS) in RAW 264.7 cells. MATERIALS AND METHODS Isolation of AzaphilonesFifteen azaphilones, specifically daldinins C, E and F (1-3) from Hypoxylon fuscum, 20,21) multiformin D (4) from H. multiforme, 11) sassafrins A-C (5-7) from Creospharia sassafras, 10) entonaemin A (8) and rubiginosins A-C (9-11) from H. rubiginosin, 22) cohaerins A and B (12, 13) from H. cohaerens, 23) rutilins A and B (14, 15) from H. rutilin, 24) were isolated from xylariaceous fungi and their structures characterized by a combination of NMR spectrometry and X-ray crystallographic analysis.Cell Culture RAW 264.7 cells, a mouse macrophage cell line, were grown in RPMI 1640 supplemented with 10% fetal bovine serum, kanamycin (50 mg/ml), and ampicillin (60 mg/ml) at 37°C in an atmosphere of 5% CO 2 and 95% air.Inhibition of NO Production of Fifteen Azaphilones One hundred microliters of RAW 264.7 cells (8ϫ10 5 cells/ ml) was pipetted into the wells of 96-well culture plates and then cultured. After 24 h incubation, 50 ml of medium containing various concentrations of each azaphilone derivative diluted in DMSO was added to each well. The final DMSO concentration was less than 0.1%. At this concentration, DMSO did not show any NO-induction without stimulation with LPS. Then, 50 ml of vehicle or LPS purified from Pantoea agglomerans (4 mg/ml) was added to each well. The cells were further in...

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confidence: 99%

Inhibition of Nitric Oxide Production in RAW 264.7 Cells by Azaphilones from Xylariaceous Fungi

Quang

Harinantenaina

Nishizawa

et al. 2006

Biological & Pharmaceutical Bulletin

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“…1), which belong to the azaphilones class, from the culture broth of this fungal strain. Azaphilones have various bioactivities such as antimicrobial activity, nitric oxide inhibition (cohaerins) [5], gp120-CD4 binding inhibition (isochromophiliones, ochrephilone, screotiorin and rubrorotiorin) [6], monoamine oxidase inhibition (luteusins, TL-1, TL-2 and chaetoviridins) [7,8] and platelet-derived growth factor binding inhibition (RP1551s) [9]. The metabolites isolated in this investigation exhibited significant cytotoxic activity against the murine P388 leukemia cell line and the human HL-60 leukemia cell line.…”

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confidence: 99%

Chaetomugilins, New Selectively Cytotoxic Metabolites, Produced by a Marine Fish-derived Chaetomium Species

et al. 2008

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Chaetomugilins AϳF have been isolated from a strain of Chaetomium globosum originally isolated from the marine fish Mugil cephalus, and their absolute stereostructures have been elucidated on the basis of spectroscopic analyses, including 1D and 2D NMR techniques, some chemical transformations and an X-ray analysis. These compounds exhibited significant growth inhibition against cultured P388 cells and HL-60 cells. In addition, chaetomugilins A, C and F showed selective cytotoxic activities against 39 human cancer cell lines.

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“…The HSQC-TOCSY data listed in Table 1 Table 1. Previously reported 5-alkenylresorcinols usually have isolated double bond(s) in the chain portion of the molecule [1,2,5]. Conjugated double bonds in the chain moiety for resorcinols are unusual.…”

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A New 5-Alkenylresorcinol Sch 725681 from Aspergillus sp.

Yang¹,

Chan²,

Terracciano

et al. 2006

J Antibiot

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A new 5-alkenylresorcinol Sch725681 (1) was isolated and identified from the culture of an Aspergillus sp. The structure elucidation of 1 was accomplished based on extensive NMR spectroscopic analyses. Compound 1 showed inhibitory activity against Saccharomyces cerevisiae (PM503) and Candida albicans (C43) with MICs of 16 and 64 mg/ml, respectively. [3]. Some resorcinols have also been reported to display antifungal [7,8], antibacterial [7], and cytotoxic activities [9].In the course of our continuing search for novel antimicrobial agents [10], we have isolated a novel antimicrobial 5-alkenylresorcinol Sch 725681 (1), from an Aspergillus sp. culture (SPRI-0784). Sch725681 was identified as a new 5-alkenylresorcinol based on extensive NMR spectroscopic analyses. In this paper, we report the isolation, structure elucidation and antimicrobial activity of 1.Fermentation studies of Aspergillus sp. culture SPRI-0784 were conducted in shake flasks. Stock cultures were maintained as frozen whole broths at Ϫ80°C in a final concentration of 10% glycerol. The germination medium contained Proteus Peptone (5.0 g/liter), NaCl (5.0 g/liter), KH 2 PO 4 (5.0 g/liter), Yeast Extract (3.0 g/liter), Cerelose (20.0 g/liter), and Soybean Grits (5.0 g/liter). The pH was adjusted to 7.0 prior to autoclaving. Each 250 ml Erlenmeyer flask containing 70 ml of this medium was inoculated with 2 ml of the stock culture. The flasks were incubated at 24°C on a rotary shaker at 250 rpm for 96 hours. This seed culture (2.5 ml) was used to inoculate a second stage seed in 250 ml Erlenmeyer flasks, each containing 70 ml of the same seed medium and the flasks were incubated as above for 96 hours. This second stage seed was then used to inoculate the fermentation medium at 5% v/v. The fermentation was carried out in 500 ml Erlenmeyer flasks, each containing 100 ml of the fermentation medium, containing Neopeptone (10.0 g/liter) and Cerelose (40.0 g/liter). The pH was adjusted to 7.4 and CaCO 3 , 4.0 g/liter was added. The flasks were incubated at 24°C on a rotary shaker at 250 rpm for 168 hours.The harvested fermentation broth (1.0 liter) was stirred with 0.2 kg of NaCl and 2.0 liters of acetonitrile (MeCN) for 15 minutes. The organic layer was separated and concentrated to a slurry in vacuo. The slurry material was absorbed onto the polymeric resin, CG161 (ϳ100 ml, Tosoh Biosep LLC, Montgomeryville, PA, USA) and the

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New Brominated and Halogen-less Derivatives and Structure-activity Relationship of Azaphilones Inhibiting gp120-CD4 Binding.

Cited by 81 publications

References 16 publications

Inhibition of Nitric Oxide Production in RAW 264.7 Cells by Azaphilones from Xylariaceous Fungi

Inhibition of Nitric Oxide Production in RAW 264.7 Cells by Azaphilones from Xylariaceous Fungi

Chaetomugilins, New Selectively Cytotoxic Metabolites, Produced by a Marine Fish-derived Chaetomium Species

A New 5-Alkenylresorcinol Sch 725681 from Aspergillus sp.

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