scholarly journals Determination of the Absolute Configuration of Bioactive Indole-Containing Pyrazino[2,1-b]quinazoline-3,6-Diones and Study of Their In Vitro Metabolic Profile

Molecules ◽  
2021 ◽  
Vol 26 (16) ◽  
pp. 5070
Author(s):  
Solida Long ◽  
Izadora L. Furlani ◽  
Juliana M. de Oliveira ◽  
Diana I. S. P. Resende ◽  
Artur M. S. Silva ◽  
...  
Keyword(s):  
Absolute Configuration ◽  
High Performance ◽  
High Resolution Mass Spectrometry ◽  
Liver Microsomes ◽  
Metabolic Studies ◽  
Metabolic Characteristics ◽  
Naturally Occurring ◽  
The Absolute ◽  
First Time

In recent decades, fungi-derived naturally occurring quinazolines have emerged as potential drug candidates. Nevertheless, most studies are conducted for bioactivity assays, and little is known about their absorption, distribution, metabolism, and elimination (ADME) properties. To perform metabolic studies, the synthesis of the naturally occurring quinazolinone, fiscalin B (1), and its chloro derivative, 4-((1H-indol-3-yl)methyl)-8,10-dichloro-1-isobutyl-1,2-dihydro-6H-pyrazino[2,1-b]quinazoline-3,6(4H)-dione (2), disclosed as an antibacterial agent, was performed in a gram scale using a microwave-assisted polycondensation reaction with 22% and 17% yields, respectively. The structure of the non-natural (+)-fiscalin B was established, for the first time, by X-ray crystallography as (1R,4S)-1, and the absolute configuration of the naturally occurring fiscalin B (-)-1 was confirmed by comparison of its calculated and experimental electronic circular dichroism (ECD) spectra as (1S,4R)-1. In vitro metabolic studies were monitored for this class of natural products for the first time by ultra-high-performance liquid chromatography (UHPLC) coupled with high-resolution mass spectrometry (HRMS). The metabolic characteristics of 1 and 2 in human liver microsomes indicated hydration and hydroxylation mass changes introduced to the parent drugs.

scholarly journals Characterization of lacosamide metabolites by UHPLC–ESI–HRMS method

2020 ◽  
Vol 32 (2) ◽  
pp. 107-116
Author(s):  
Maciej Gawlik ◽  
Robert Skibiński ◽  
Łukasz Komsta
Keyword(s):  
Human Liver ◽  
High Performance ◽  
High Resolution Mass Spectrometry ◽  
Parent Compound ◽  
Liver Microsomes ◽  
Complementary Technique ◽  
Polar Metabolite ◽  
Simulation Techniques

In this study, the in vitro phase I metabolism of lacosamide was characterized with the use of ultra-high-performance liquid chromatography combined with high-resolution mass spectrometry (quadrupole time-of-flight). The use of two metabolism simulation techniques (photocatalysis and human liver microsomes) allowed the characterization of a polar metabolite of parent compound, not yet described. The experiment with the participation of HLM gave the ability to describe the full liver metabolic pathway of lacosamide. It has been proven that this molecule undergoes deacetylation, demethylation, and during liver tissue metabolism. Photocatalysis with the use of a TiO2 catalyst was proved to be a complementary technique in mimicking in vitro drug metabolism.

scholarly journals Screening and Identification of the Main Metabolites of Schisantherin a In Vivo and In Vitro by Using UHPLC-Q-TOF-MS/MS

Molecules ◽  
2020 ◽  
Vol 25 (2) ◽  
pp. 258 ◽  
Author(s):  
Wei Feng ◽  
Ling-Yu Zhou ◽  
Rui-Feng Mu ◽  
Le Gao ◽  
Bing-Yuan Xu ◽  
...  
Keyword(s):  
Metabolic Pathways ◽  
High Performance ◽  
Liver Microsomes ◽  
Rat Liver Microsomes ◽  
Sprague Dawley ◽  
First Time ◽  
Schisantherin A ◽  
Tof Ms

Schisantherin A is an active ingredient originating from Schisandra chinensis (Turcz.) which has hepatoprotective and anti-oxidation activities. In this study, in vitro metabolisms investigated on rat liver microsomes (RLMs) and in vivo metabolisms explored on male Sprague Dawley rats of Schisantherin A were tested, respectively. The metabolites of Schisantherin A were identified using ultra-high-performance liquid chromatography coupled with hybrid triple quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS/MS). Based on the method, 60 metabolites were successfully identified and structurally characterized including 48 phase-I and 12 phase-II metabolites. Among the metabolites, 45 metabolites were reported for the first time. Moreover, 56 and eight metabolites were detected in urine and bile and 19 metabolites were identified in rats’ plasma. It demonstrated that hepatic and extra-hepatic metabolic pathways were both involved in Schisantherin A biotransformation in rats. Five in vitro metabolites were structurally characterized for the first time. The results indicated that the metabolic pathways mainly include oxidation, reduction, methylation, and conjugation with glucuronide, taurine, glucose, and glutathione groups. This study provides a practical strategy for rapidly screening and identifying metabolites, and the results provide basic data for future pharmacological and toxicology studies of Schisantherin A and other lignin ingredients.

scholarly journals In vitro glucuronidation of trans-Piceid and trans-Piceatannol by human liver microsomes

OENO One ◽  
2008 ◽  
Vol 42 (4) ◽  
pp. 241
Author(s):  
Caroline Henry-Vitrac ◽  
Thomas Richard ◽  
Alexis Desmoulière ◽  
Jean-Pierre Monti ◽  
Jean-Michel Mérillon ◽  
...  
Keyword(s):  
Human Liver ◽  
Red Wine ◽  
Biological Activities ◽  
Liver Microsomes ◽  
Human Liver Microsomes ◽  
Beneficial Effects ◽  
Naturally Occurring ◽  
Phenolic Substances ◽  
First Time

<p style="text-align: justify;"><strong>Aims</strong> : The aim of the present investigation was to establish glucuronidation of trans-resveratrol derivates in the liver. Stilbenes are naturally occurring polyphenolic compounds which have been reported to have potential preventive activities in human diseases. Trans-stilbenes, mainly found in grapes and red wine, are important in terms of biological activities. However, little is known about the metabolism of these compounds in human.</p><p style="text-align: justify;"><strong>Methods and results</strong> : The glucuronoconjugation of stilbenes was investigated using human liver microsomes and the structure of new metabolites was characterized by LC-MS and proton NMR. For the first time, the structure of the metabolites of trans-piceid and trans-piceatannol was established. The reaction led to the formation of two glucuronides for trans-piceid and three for trans-piceatannol.</p><p style="text-align: justify;"><strong>Significance and impact of study</strong>: This study is of particular relevance since the phenolic substances of red wine (especially stilbenes) might be responsible for the potential beneficial effects of moderate and regular wine consumption.</p>

scholarly journals Screening of flavonoid aglycons’ metabolism mediated by the human liver cytochromes P450

2019 ◽  
Vol 69 (4) ◽  
pp. 541-562 ◽  
Author(s):  
Goran Benković ◽  
Mirza Bojić ◽  
Željan Maleš ◽  
Siniša Tomić
Keyword(s):  
Human Liver ◽  
High Performance ◽  
High Resolution Mass Spectrometry ◽  
Biological Effects ◽  
Cytochromes P450 ◽  
Liver Microsomes ◽  
Recombinant Enzymes ◽  
Aromatic Hydroxylation ◽  
Metabolic Reactions

Abstract Biological effects of flavonoids have been extensively studied in the last 80 years. As flavonoids represent a rather large group of compounds, data on metabolic biotransformations of these compounds is relatively limited to those well studied. The objective of this study was to screen the metabolism of 30 selected flavonoid aglycons mediated by the most relevant metabolic enzymes, human liver cytochromes P450. For this purpose, in vitro experiments with human liver microsomes and recombinant enzymes were conducted. To evaluate flavonoid’s metabolism and structure of the products, high-performance liquid chromatography coupled with high-resolution mass spectrometry was used. Out of 30 flavonoids, 15 were susceptible to oxidative metabolism mediated by cytochromes P450. Dominant reactions were aromatic hydroxylation and O-demethylation, or a combination of these reactions. The dominant enzyme responsible for the observed metabolic reactions is CYP1A2, whereas other human liver cytochromes P450, namely, CYP2C19, CYP2D6, CYP2E1 and CYP3A4, contribute to flavonoid metabolism to a lesser degree. These results, to some extent, contribute to the understanding of the metabolism of constituents found in antioxidant dietary supplements and their possible interactions with other xenobiotics, i.e., medicinal products.

scholarly journals Nontargeted Metabolomics by High-Resolution Mass Spectrometry to Study the In Vitro Metabolism of a Dual Inverse Agonist of Estrogen-Related Receptors β and γ, DN203368

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 776
Author(s):  
Sin-Eun Kim ◽  
Seung-Bae Ji ◽  
Euihyeon Kim ◽  
Minseon Jeong ◽  
Jina Kim ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
High Resolution ◽  
Human Liver ◽  
High Resolution Mass Spectrometry ◽  
Liver Microsomes ◽  
Human Liver Microsomes ◽  
Rat Liver Microsomes ◽  
High Resolution Mass ◽  
Resolution Mass

DN203368 ((E)-3-[1-(4-[4-isopropylpiperazine-1-yl]phenyl) 3-methyl-2-phenylbut-1-en-1-yl] phenol) is a 4-hydroxy tamoxifen analog that is a dual inverse agonist of estrogen-related receptor β/γ (ERRβ/γ). ERRγ is an orphan nuclear receptor that plays an important role in development and homeostasis and holds potential as a novel therapeutic target in metabolic diseases such as diabetes mellitus, obesity, and cancer. ERRβ is also one of the orphan nuclear receptors critical for many biological processes, such as development. We investigated the in vitro metabolism of DN203368 by conventional and metabolomic approaches using high-resolution mass spectrometry. The compound (100 μM) was incubated with rat and human liver microsomes in the presence of NADPH. In the metabolomic approach, the m/z value and retention time information obtained from the sample and heat-inactivated control group were statistically evaluated using principal component analysis and orthogonal partial least-squares discriminant analysis. Significant features responsible for group separation were then identified using tandem mass spectra. Seven metabolites of DN203368 were identified in rat liver microsomes and the metabolic pathways include hydroxylation (M1-3), N-oxidation (M4), N-deisopropylation (M5), N,N-dealkylation (M6), and oxidation and dehydrogenation (M7). Only five metabolites (M2, M3, and M5-M7) were detected in human liver microsomes. In the conventional approach using extracted ion monitoring for values of mass increase or decrease by known metabolic reactions, only five metabolites (M1-M5) were found in rat liver microsomes, whereas three metabolites (M2, M3, and M5) were found in human liver microsomes. This study revealed that nontargeted metabolomics combined with high-resolution mass spectrometry and multivariate analysis could be a more efficient tool for drug metabolite identification than the conventional approach. These results might also be useful for understanding the pharmacokinetics and metabolism of DN203368 in animals and humans.

scholarly journals Phytochemical Study and In Vitro Screening Focusing on the Anti-Aging Features of Various Plants of the Greek Flora

Antioxidants ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1206
Author(s):  
Aimilia D. Sklirou ◽  
Maria T. Angelopoulou ◽  
Aikaterini Argyropoulou ◽  
Eliza Chaita ◽  
Vasiliki Ioanna Boka ◽  
...  
Keyword(s):  
Plant Species ◽  
High Performance ◽  
High Resolution Mass Spectrometry ◽  
Ultra Performance Liquid Chromatography ◽  
Skin Aging ◽  
Rosa Damascena ◽  
Phytochemical Study ◽  
Age Related

Skin health is heavily affected by ultraviolet irradiation from the sun. In addition, senile skin is characterized by major changes in the collagen, elastin and in the hyaluronan content. Natural products (NPs) have been shown to delay cellular senescence or in vivo aging by regulating age-related signaling pathways. Moreover, NPs are a preferable source of photoprotective agents and have been proven to be useful against the undesirable skin hyperpigmentation. Greek flora harvests great plant diversity with approximately 6000 plant species, as it has a wealth of NPs. Here, we report an extensive screening among hundreds of plant species. More than 440 plant species and subspecies were selected and evaluated. The extracts were screened for their antioxidant and anti-melanogenic properties, while the most promising were further subjected to various in vitro and cell-based assays related to skin aging. In parallel, their chemical profile was analyzed with High-Performance Thin-Layer Chromatography (HPTLC) and/or Ultra-Performance Liquid Chromatography High-Resolution Mass Spectrometry (UPLC-HRMS). A variety of extracts were identified that can be of great value for the cosmetic industry, since they combine antioxidant, photoprotective, anti-melanogenic and anti-aging properties. In particular, the methanolic extracts of Sideritis scardica and Rosa damascena could be worthy of further attention, since they showed interesting chemical profiles and promising properties against specific targets involved in skin aging.

scholarly journals Enzymatic activity in turkey, duck, quail and chicken liver microsomes against four human cytochrome P450 prototype substrates and aflatoxin B1

2011 ◽  
Vol 1 (1) ◽  
pp. 4 ◽  
Author(s):  
Hansen W. Murcia ◽  
Gonzalo J. Díaz ◽  
Sandra Milena Cepeda
Keyword(s):  
Cytochrome P450 ◽  
Aflatoxin B1 ◽  
Enzyme Activities ◽  
High Performance ◽  
Biochemical Characterization ◽  
Liver Microsomes ◽  
Cytochrome P450 Enzymes ◽  
Catalytic Rate

Cytochrome P450 enzymes (CYP) are a group of monooxygenases able to biotransform several kinds of xenobiotics including aflatoxin B1 (AFB1), a highly toxic mycotoxin. These enzymes have been widely studied in humans and others mammals, but there is not enough information in commercial poultry species about their biochemical characteristics or substrate specificity. The aim of the present study was to identify CYPs from avian liver microsomes with the use of prototype substrates specific for human CYP enzymes and AFB1. Biochemical characterization was carried out in vitro and biotransformation products were detected by high-performance liquid chromatography (HPLC). Enzymatic constants were calculated and comparisons between turkey, duck, quail and chicken activities were done. The results demonstrate the presence of four avian ortholog enzyme activities possibly related with a CYP1A1, CYP1A2, CYP2A6 (activity not previously identified) and CYP3A4 poultry orthologs, respectively. Large differences in enzyme kinetics specific for prototype substrates were found among the poultry species studied. Turkey liver microsomes had the highest affinity and catalytic rate for AFB1 whereas chicken enzymes had the lowest affinity and catalytic rate for the same substrate. Quail and duck microsomes showed intermediate values. These results correlate well with the known in vivo sensitivity for AFB1 except for the duck. A high correlation coefficient between 7-ethoxyresorufin-Odeethylase (EROD) and 7-methoxyresorufin- O-deethylase (MROD) activities was found in the four poultry species, suggesting that these two enzymatic activities might be carried out by the same enzyme. The results of the present study indicate that four prototype enzyme activities are present in poultry liver microsomes, possibly related with the presence of three CYP avian orthologs. More studies are needed in order to further characterize these enzymes.

ChemInform Abstract: Total Synthesis and Determination of the Absolute Configuration of FD-838, a Naturally Occurring Azaspirobicyclic Product.

ChemInform ◽  
2009 ◽  
Vol 40 (47) ◽  
Author(s):  
Yujiro Hayashi ◽  
Kuppusamy Sankar ◽  
Hayato Ishikawa ◽  
Yuriko Nozawa ◽  
Kazutoshi Mizoue ◽  
...  
Keyword(s):  
Total Synthesis ◽  
Absolute Configuration ◽  
Naturally Occurring ◽  
The Absolute

scholarly journals Human Biomonitoring of T-2 Toxin, T-2 Toxin-3-Glucoside and Their Metabolites in Urine through High-Resolution Mass Spectrometry

Toxins ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 869
Author(s):  
Alfonso Narváez ◽  
Luana Izzo ◽  
Noelia Pallarés ◽  
Luigi Castaldo ◽  
Yelko Rodríguez-Carrasco ◽  
...  
Keyword(s):  
High Performance ◽  
High Resolution Mass Spectrometry ◽  
Human Biomonitoring ◽  
Italian Population ◽  
South Italy ◽  
Almost All ◽  
Low Prevalence ◽  
Frequent Exposure ◽  
Mean Concentration

The metabolic profile of T-2 toxin (T-2) and its modified form T-2-3-glucoside (T-2-3-Glc) remain unexplored in human samples. Therefore, the present study aimed to investigate the presence of T-2, T-2-3-Glc and their respective major metabolites in human urine samples (n = 300) collected in South Italy through an ultra-high performance liquid chromatography (UHPLC) coupled to Q-Orbitrap-HRMS methodology. T-2 was quantified in 21% of samples at a mean concentration of 1.34 ng/mg Crea (range: 0.22–6.54 ng/mg Crea). Almost all the major T-2 metabolites previously characterized in vitro were tentatively found, remarking the occurrence of 3′-OH-T-2 (99.7%), T-2 triol (56%) and HT-2 (30%). Regarding T-2-3-Glc, a low prevalence of the parent mycotoxin (1%) and its metabolites were observed, with HT-2-3-Glc (17%) being the most prevalent compound, although hydroxylated products were also detected. Attending to the large number of testing positive for T-2 or its metabolites, this study found a frequent exposure in Italian population.

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