18 research outputs found

    The retention time, predicted elemental compositions, observed mass and calculated mass, characteristic fragment ions, and description of metabolites of WS070117 in rat urine.

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    <p>The retention time, predicted elemental compositions, observed mass and calculated mass, characteristic fragment ions, and description of metabolites of WS070117 in rat urine.</p

    Structure Elucidation of the Metabolites of 2', 3', 5'-Tri-<i>O</i>-Acetyl-<i>N</i><sub>6</sub>-(3-Hydroxyphenyl) Adenosine in Rat Urine by HPLC-DAD, ESI-MS and Off-Line Microprobe NMR

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    <div><p>2', 3', 5'-tri-<i>O</i>-acetyl-<i>N<sub>6</sub></i>-(3-hydroxyphenyl) adenosine (also known as WS070117) is a new adenosine analog that displays anti-hyperlipidemic activity both <i>in vitro</i> and <i>in vivo</i> experiments as shown in many preliminary studies. Due to its new structure, little is known about the metabolism of WS070117. Hence, the <i>in vivo</i> metabolites of WS070117 in rat urine following oral administration were investigated. Identification of the metabolites was conducted using the combination of high-performance liquid chromatography (HPLC) coupled with diode array detector (DAD), ion trap electrospray ionization-mass spectrometry (ESI-MS), and off-line microprobe nuclear magnetic resonance (NMR) measurements. Seven metabolites were obtained as pure compounds at the sub-milligram to milligram levels. Results of structure elucidation unambiguously revealed that the phase I metabolite, <i>N<sub>6</sub></i>-(3-hydroxyphenyl) adenosine (M8), was a hydrolysate of WS070117 by hydrolysis on the three ester groups. <i>N<sub>6</sub></i>-(3-hydr-oxyphenyl) adenine (M7), also one of the phase I metabolites, was the derivative of M8 by the loss of ribofuranose. In addition to two phase I metabolites, there were five phase II metabolites of WS070117 found in rat urine. 8-hydroxy-<i>N<sub>6</sub></i>-(3-hydroxy-phenyl) adenosine (M6) was the product of M7 by hydrolysis at position 8. The other four were elucidated to be <i>N<sub>6</sub></i>-(3-<i>O-β</i>-D-glucuronyphenyl) adenine (M2), <i>N<sub>8</sub></i>-hydroxy-<i>N<sub>6</sub></i>-(3-<i>O</i>-sulfophenyl) adenine (M3), <i>N<sub>6</sub></i>-(3-<i>O-β</i>-D-glucuronyphenyl) adenosine (M4), and <i>N<sub>6</sub></i>-(3-<i>O</i>- sulfophenyl) adenosine (M5). Phase II metabolic pathways were proven to consist of hydroxylation, glucuronidation and sulfation. This study provides new and valuable information on the metabolism of WS070117, and also demonstrates the HPLC/MS/off-line microprobe NMR approach as a robust means for rapid identification of metabolites.</p></div

    Beneficial Metabolic Effects of 2′,3′,5′-Triacetyl‑N<sub>6</sub>‑(3-hydroxylaniline) adenosine in Multiple Biological Matrices and Intestinal Flora of Hyperlipidemic Hamsters

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    Hyperlipidemia is one of the main causes of obesity, type 2 diabetes mellitus (T2DM), and atherosclerosis. The adenosine derivative, 2′,3′,5′-triacetyl-N<sub>6</sub>-(3-hydroxylaniline) adenosine (IMM-H007) is an effective lipid-lowering compound that has important implications for the development of lipid-lowering drugs. Metabolomic analysis based on <sup>1</sup>H NMR was used to monitor dynamic changes in diverse biological media including serum, liver, urine, and feces in response to high-fat diet (HFD) and IMM-H007 treatments. Ultraperformance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) and gas chromatography (GC) analyses were performed to quantify the bile acids and fatty acids in the liver and feces. Fecal microbiome profiling was performed using Illumina sequencing of the 16S rRNA (<i>16S rRNA</i>) gene. IMM-H007 improved the metabolism of carbohydrate, ketone bodies, fatty acids, amino acids, and bile acids in hyperlipidemic hamsters. The correlation between metabolite changes was explored in different biological media. Significant changes in gut microbiota were observed in the HFD and IMM-H007 treatment groups. In the HFD group at the phylum level, we found high levels of the Firmicutes genus and low levels of Bacteroidetes. In contrast, the administration of IMM-H007 reversed the levels of Firmicutes and Bacteroidetes. This reversal suggested that IMM-H007 may have the ability to regulate the composition of the gut flora. We also analyzed the correlation between the gut flora and the metabolites. Our results indicate that IMM-H007 treatment improves the hyperlipidemic metabolism and the structure of the gut microbiota in hyperlipidemic hamsters

    <sup>1</sup>H NMR derived HSQC (A) and HMBC (B) spectra of <i>N</i><sub>8</sub>-hydroxy-<i>N</i><sub>6</sub>-(3-<i>O</i>-sulfophenyl) adenine (structure see formula insert).

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    <p><b>A</b> secondary metabolite in rat urine following WS070117 oral administration. The NMR spectra were obtained in deuterated DMSO on a 500 MHz NMR spectrometer, equipped with a 1.7 PA TXI microprobe. (A) HSQC (acquisition time: 2 h): red cross-peaks are stemming from CH, CH<sub>2</sub> and CH<sub>3</sub> protons. (B) HMBC (acquisition time: 6 h): the correlation information derived from the marked cross-peaks is summarized in the formula insert.</p

    HPLC chromatogram of WS010117 metabolites in urine of control (A) and administrated (B) rats at 299 nm.

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    <p>Peak 1: 3.60 min (M1); 2: 14.15 min (M2); 3: 21.58 min (M3); 4: 23.25 min (M4); 5: 29.48 min (M5); 6: 47.68 min (M6); 7: 48.73 min (M7); 8: 49.44 min (M8).</p
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