Synthesis and antihepatotoxic and antiproliferative activities of di- and tri-O-caffeoylquinic acid derivatives

Methyl di- and tri-O-caffeoylquinates were synthesized by esterification of methyl quinate with di-O-acetylcaffeoyl chloride, following deprotection of the acetyl groups. Moreover, 4,5-di-O-caffeoylquinic acid was synthesized by esterification of quinide with di-O-acetylcaffeoyl chloride, followed by a hydrolysis of product quinide. These synthetic compounds were tested for their hepatoprotective activity on _D-galactosamine (_D-GalN)/tumor necrosis factor-α (TNF- α)-induced cell death in primary cultured mouse hepatocytes, which possessed significant hepatoprotective activity concentration-dependently. The activity was enhanced by the presence of caffeoyl group. On the other hand, they showed only weak antiproliferative activities against murine colon 26-L5 carcinoma, human HT-1080 fibrosarcoma, murine B16-BL6 melanoma, and human lung carcinoma A-549 cells. メチルジおよびトリカフェオイルキネート化合物1-4は,メチルキネート6をジアセチルカフェオイルクロライド7でエステル化した後,アセチル基の脱保護によって合成した。さらに,4,5-ジカフェオイルキナ酸5は,キニド8を7とエステル化して生成したキニド8aの加水分解により合成した。これらの合成した化合物1-5を用いてマウス初代培養肝細胞の_D-GalN/TNF-α誘発肝細胞死における肝保護活性の試験を行ったところ,濃度依存的な肝保護活性が認められた。その活性はカフェオイル基の存在により増強された。一方,これらの化合物1-5はマウス26-L5大腸癌腫,ヒトHT-1080繊維芽肉腫,マウスB16-BL6黒色種,及びヒトA-549肺癌腫に対し弱い細胞増殖抑制活性を示した

Synthesis and antihepatotoxic and antiproliferative activities of di- and tri-O-caffeoylquinic acid derivatives

Methyl di- and tri-O-caffeoylquinates were synthesized by esterification of methyl quinate with di-O-acetylcaffeoyl chloride, following deprotection of the acetyl groups. Moreover, 4,5-di-O-caffeoylquinic acid was synthesized by esterification of quinide with di-O-acetylcaffeoyl chloride, followed by a hydrolysis of product quinide. These synthetic compounds were tested for their hepatoprotective activity on _D-galactosamine (_D-GalN)/tumor necrosis factor-\u3b1 (TNF- \u3b1)-induced cell death in primary cultured mouse hepatocytes, which possessed significant hepatoprotective activity concentration-dependently. The activity was enhanced by the presence of caffeoyl group. On the other hand, they showed only weak antiproliferative activities against murine colon 26-L5 carcinoma, human HT-1080 fibrosarcoma, murine B16-BL6 melanoma, and human lung carcinoma A-549 cells.Peer reviewed: YesNRC publication: N

Metabolism of Strobilurins by Wheat Cell Suspension Cultures

Strobilurin fungicides are a leading class of antifungal chemicals used today in agricultural applications. Although degradation of some strobilurin fungicides has been assessed in plant residues, little information has appeared in the literature concerning the rates of metabolism of these fungicides in plants. In this study, we explored plant metabolism of three strobilurin fungicides, azoxystrobin, kresoxim-methyl, and trifloxystrobin, using wheat cell suspension cultures. Trifloxystrobin and kresoxim-methyl were completely metabolized within 24 h, whereas the metabolism of azoxystrobin was relatively slow with half-lives up to 48 h depending on specific experimental conditions. Metabolic rates of these fungicides were affected by the amounts of compound and cells added to the media. Structural analysis of metabolites of trifloxystrobin and kresoxim-methyl by high-resolution mass spectrometry (HRMS) and nuclear magnetic resonance spectroscopy (NMR) indicated that trifloxystrobin was first demethylated followed by subsequent hydroxylation, whereas kresoxim-methyl was largely demethylated. In contrast, a number of minor metabolites of azoxystrobin were present suggesting a differential metabolism of strobilurins by wheat cells

Quadranosides I-V, new triterpene glucosides from the seeds of Combretum quadrangulare

Five new triterpene glucosides, quadranosides I 12V (1 125), have been isolated from a MeOH extract of the seeds of Combretum quadrangulare, together with 13 known compounds. The structures of compounds 1 125 were elucidated on the basis of spectroscopic analysis. Among the new triterpene glucosides, three compounds (1, 2, 5) showed significant hepatoprotective effects against d-galactosamine (d-GalN)/tumor necrosis factor-\u3b1 (TNF-\u3b1)-induced cell death in primary cultured mouse hepatocytes.Peer reviewed: YesNRC publication: N

Screening of Chinese herbal drug extracts for inhibitory activity on nitric oxide production and identification of an active compound of Zanthoxylum bungeanum

Sixty-eight water and methanol extracts from 34 Chinese herbal drugs, most of which are used for inflammatory diseases, were screened for their inhibitory effects on nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated J774.1 macrophages and in LPS/interferon (IFN)-\u3b3-stimulated mouse peritoneal exudate macrophages. Among the extracts, methanol extracts of Myristica fragrans, Plantago asiatica, Rubia cordifolia, and Zanthoxylum bungeanum showed significant inhibition in J774.1 macrophages, while in mouse peritoneal exudate macrophages, water extracts of Ru. cordifolia and Scutellaria baicalensis and methanol extracts of Angelica megaphylla, My. fragrans, and Z. bungeanum inhibited the NO production. Among them, inhibition of water extract of Sc. baicalensis was found to be mainly due to direct scavenging of NO radicals, through an examination of its scavenging activity on PAPA NONOate-generated NO radicals, while water extract of Ru. cordifolia and methanol extracts of An. megaphylla, My. fragrans, P. asiatica, and Z. bungeanum showed inhibition on iNOS mRNA expression. At last, an inhibitory compound on iNOS mRNA expression was isolated from a methanol extract of Z. bungeanum and identified as 4-O-\u3b2-d-glucopyranosyldihydroferulic acid by NMR spectral analyses and chemical synthesis.Peer reviewed: YesNRC publication: N

Cholesterol Import by Aspergillus fumigatus and Its Influence on Antifungal Potency of Sterol Biosynthesis Inhibitors

High mortality rates from invasive aspergillosis in immunocompromised patients are prompting research toward improved antifungal therapy and better understanding of fungal physiology. Herein we show that Aspergillus fumigatus, the major pathogen in aspergillosis, imports exogenous cholesterol under aerobic conditions and thus compromises the antifungal potency of sterol biosynthesis inhibitors. Adding serum to RPMI medium led to enhanced growth of A. fumigatus and extensive import of cholesterol, most of which was stored as ester. Growth enhancement and sterol import also occurred when the medium was supplemented with purified cholesterol instead of serum. Cells cultured in RPMI medium with the sterol biosynthesis inhibitors itraconazole or voriconazole showed retarded growth, a dose-dependent decrease in ergosterol levels, and accumulation of aberrant sterol intermediates. Adding serum or cholesterol to the medium partially rescued the cells from the drug-induced growth inhibition. We conclude that cholesterol import attenuates the potency of sterol biosynthesis inhibitors, perhaps in part by providing a substitute for membrane ergosterol. Our findings establish significant differences in sterol homeostasis between filamentous fungi and yeast. These differences indicate the potential value of screening aspergillosis antifungal agents in serum or other cholesterol-containing medium. Our results also suggest an explanation for the antagonism between itraconazole and amphotericin B, the potential use of Aspergillus as a model for sterol trafficking, and new insights for antifungal drug development

Phoslactomycins from <i>Streptomyces</i> sp. MLA1839 and Their Biological Activities

Phoslactomycins H (<b>1</b>) and I (<b>2</b>), two new members of the phoslactomycin class of chemistry, were isolated from <i>Streptomyces</i> sp. MLA1839 on the basis of their antifungal activities. Their structures were elucidated using extensive NMR spectroscopy and mass spectrometry. Phoslactomycin H (<b>1</b>) featured a rare and unprecedented <i>N</i>,<i>N</i>-dimethylamine substitution at C-4 and existed as a hydroxy acid rather than the more common lactone. Herein, we report the structure of these compounds and their biological activities