Artemisinin (ART) is a highly effective antimalarial agent isolated from the traditional Chinese herb Qinghao. Metabolism of ART and its derivatives in the body is one of the most pressing issues for pharmaceutical scientists. Herein, an efficient in vitro microorganism model for simulation of metabolism of ART in vivo was developed employing Cunninghamella elegans. Metabolites in the microbial transformation system and plasma of mice pre-administrated ART orally were analyzed by ultra-performance liquid chromatography (UPLC)-electrospray ionization (ESI)-quadrupole time-of-flight (Q-TOF)-mass spectrometry (MSE) combined with UNIFI software. Thirty-two metabolites were identified in vitro and 23 were identified in vivo. After comparison, 16 products were found to be common to both models including monohydroxylated ART, dihydroxylated ART, deoxyartemisinin, hydroxylated deoxyartemisinin, hydroxylated dihydroartemisinin (DHA), and hydroxylated deoxy-DHA. These results revealed that C. elegans CICC 40250 functioned as an appropriate model to mimic ART metabolism in vivo. Moreover, an overall description of metabolites of ART from C. elegans CICC 40250 has been provided. Notably, DHA was detected and identified as a metabolite of ART in mouse plasma for the first time.
10-deoxoartemisinin is a semisynthetic derivative of artemisinin that lacks a lactone carbonyl group at the 10-position, and has stronger antimalarial properties than artemisinin. However, 10-deoxoartemisinin has limited utility as a therapeutic agent because of its low solubility and bioavailability. Hydroxylated 10-deoxoartemisinins are a series of properties-improved derivatives. Via microbial transformation, which can hydroxylate 10-deoxoartemisinin at multiple sites, the biotransformation products of 10-deoxoartemisinin have been investigated in this paper. Using ultra-performance liquid chromatography-electrospray ionization-quadrupole time-of-flight mass spectrometry (UPLC-ESI-Q-TOF-MSE) combined with UNIFI software, products of microbial transformation of 10-deoxoartemisinin were rapidly and directly analyzed. The hydroxylation abilities of nine microorganisms were compared using this method. All of the microorganisms evaluated were able to hydroxylate 10-deoxoartemisinin, and a total of 35 hydroxylated products were identified. These can be grouped into dihydroxylated 10-deoxoartemisinins, monohydroxylated 10-deoxoartemisinins, hydroxylated dehydrogenated 10-deoxoartemisinins, and hydroxylated hydrogenated 10-deoxoartemisinins. Cunninghamella echinulata and Cunninghamella blakesleeana are able to hydroxylate 10-deoxoartemisinin, and their biotransformation products are investigated here for the first time. Cunninghamella elegans CICC 40250 was shown to most efficiently hydroxylate 10-deoxoartemisinin, and could serve as a model organism for microbial transformation. This method could be used to generate additional hydroxylated 10-deoxoartemisinins for further research.
Ultraperformance convergence chromatography is an environmentally friendly analytical technique for dramatically reducing the use of organic solvents compared to conventional chromatographic methods. In this study, a rapid and sensitive ultraperformance convergence chromatography method was firstly established for quantification of thymol and carvacrol, two positional isomers of a major bioactive in the volatile oil of Thymi herba, the dried leaves and flowers of Thymus mongolicus or Thymus przewalskii, known in China as “Dijiao.” Using a TrefoilTM CEL1 column, thymol and carvacrol were separated in less than 2.5 min and resolution was enhanced. The method was validated with respect to precision, accuracy, and linearity according to the National Medical Products Administration guidelines. The optimized method exhibited good linear correlation (r = 0.9998−0.9999), excellent precision (relative standard deviations (RSDs) < 1.50%), and acceptable recoveries (87.29–102.89%). The limits of detection for thymol and carvacrol were 1.31 and 1.57 ng/L, respectively, while their corresponding limits of quantification were 2.63 and 3.14 ng/L. Finally, the quantities of the two compounds present in 16 T. mongolicus and four T. przewalskii samples were successfully evaluated by employing the developed method. It is hoped that the results of this study will serve as a guideline for the quality control of Thymi herba.
Indoles, especially multisubstituted ones, are privileged scaffolds found widely in natural products, bioactive molecules, fine chemicals, and organic functional materials. Although several intramolecular electrochemical cyclization reactions of vinyl anilines to construct indoles have been reported in recent years, the intermolecular process between simple anilines and other readily available synthons, even though dominant, remains relatively unexplored. Herein, we report the intermolecular electro-oxidative cycloaddition of anilines and commercially available 1,3-dicarbonyl compounds. This method provides an alternative route for the synthesis of a broad range of multisubstituted indoles without a transition-metal catalyst or external chemical oxidant.
A simple and effective method for the simultaneous quantitative analysis of six caffeoylquinic acids (CAs) in Matricaria chamomilla L. (M. chamomilla) using high-performance liquid chromatography (HPLC) with diode-array detection (DAD) was established. The chromatographic separation was performed on a Waters XBridge Shield RP C18 column (4.6 mm × 250 mm, 5 μm) with the mobile phase of acetonitrile (0.5% phosphoric acid) and water (0.5% phosphoric acid) using a gradient elution at a flow rate of 1.0 mL/min and UV detection at 327 nm. The correlation coefficients of all analytes were 0.999, and the results showed excellent linearity. The lower limits of detection (LLOD) and quantification (LLOQ) of all analytes fall within the range of 0.014∼0.017 μg/mL and 0.068∼0.086 μg/mL, respectively. The extraction recoveries of all analytes fall within the range of 100.74%∼101.55%, with relative standard deviation not exceeding 2.83%. The intraday and interday precisions fall within the range of 0.03%∼0.65% and 0.02%∼0.09%, respectively. This validated method was successfully applied to the investigation of 34 samples of M. chamomilla collected from different geographical areas. The results showed that the established method is appropriate for the analysis of the six CAs in M. chamomilla and helpful for quality assessment of capitula of M. chamomilla (CMC), whole herb of M. chamomilla (WHMC), and related herbal formulas.
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