Metabolic Profile of C-Prenyl Coumarins Using Mass Spectrometry-Based Metabolomics

C-prenyl coumarins (C-PYCs) are compounds with similar structures and various bioactivities, which are widely distributed in medicinal plants. Until now, the metabolic characterizations of C-PYCs and the relationship between metabolism and bioactivities remain unclear. In this study, ultra-performance chromatography electrospray ionization quadrupole time-of-flight mass spectrometry-based metabolomics (UPLC-ESI-QTOF-MS) was firstly used to determine the metabolic characterizations of three C-PYCs, including meranzin hydrate (MH), isomeranzin (ISM), and meranzin (MER). In total, 52 metabolites were identified, and all of them were found to be novel metabolites. Among these metabolites, 10 were from MH, 22 were from ISM, and 20 were from MER. The major metabolic pathways of these C-PYCs were hydroxylation, dehydrogenation, demethylation, and conjugation with cysteine, N-acetylcysteine, and glucuronide. The metabolic rate of MH was much lower than ISM and MER, which was only 27.1% in MLM and 8.7% in HLM, respectively. Additionally, recombinant cytochrome P450 (CYP) screening showed that CYP1A1, 2B6, 3A4, and 3A5 were the major metabolic enzymes involved in the formation of metabolites. Further bioactivity assays indicated that all of these three C-PYCs exhibited anti-inflammatory activity, but the effects of ISM and MER were slightly higher than MH, accompanied by a significant decrease in inflammatory cytokines transcription induced by lipopolysaccharide (LPS) in macrophages RAW 264.7. Taken together, the metabolic characterizations of the three C-PYCs suggested that the side chain of the prenyl group may impact the metabolism and biological activity of C-PYCs.

Chemical Composition and Cytotoxic Effect of Prangos turcica A. Duran, M. Sagiroglu & H. Duman

In addition to the antiflatulent, emollient, antifungal, antihemorrhoidal, antioxidant, anthelmintic effects, Prangos species have been used to stop bleeding and for the treatment of wounds and scars in central Asia and Turkey. In the present study, the compounds were isolated using chromatographic methods, and their structures were identified by 1H NMR and direct comparison with the reference compounds where available. Fifteen known coumarins were isolated from the dichloromethane extract as osthol, murraol, auraptenol, peroxyauraptenol, 4'-senecioiloxyosthol, meranzin hydrate, scopoletin, umbelliferone, isoimperatorin, oxypeucedanin, oxypeucedanin hydrate, oxypeucedanin methanolate, gosferol, psoralen, and marmesin. The cytotoxic activities of all isolated compounds from dichloromethane extract of P. turcica roots were evaluated using MTT assay on human adenocarcinoma (prostate PC-3) cells. 4'-senecioiloxyosthol, oxypeucedanin methanolate, gosferol, psoralen, peroxyauraptenol and marmesin were tested for the first time on the PC-3 cell line. Osthol and peroxyauraptenol showed the highest cytotoxic activity with IC50 values of 65 and 72 µg/mL, respectively. Additionally, auraptenol, scopoletin, gosferol, psoralen, 4'-senecioiloxyosthol and dichloromethane extract of root part (Pt/R/DCM) demonstrated moderate to low cytotoxic activity. Consequently, the most potent compounds, osthol and peroxyauraptenol, may be used as a lead compound to develop effective drug substances to treat prostate cancer.

Prokinetic meranzin hydrate from Chaihu-Shugan-San improves depression-like behaviors and hypomotility in rats via ghrelin and neurocircuitry

Background Depression and functional dyspepsia (FD) are characterized by comorbidity, overlapping depression, and nausea. The pathogenesis of depression and FD is mediated by α2-adrenoreceptor and/or ghrelin. Antidepressant (A) or prokinetic (P) agents are numerous, but few have been investigated in this context. Ancient Gan-zhu-shu-xie (GZSX), whose representative traditional Chinese medicine(TCM) is Chaihu-Shugan-San (CSS), may exert antidepressant effects with prokinetic meranzin hydr-ate (MH) via α2-adrenoreceptors in the acute forced swimming (FS) test in rats.Therefore, the main aim of the study is to investigate the acute antidepressant and prokinet-ic effects of CSS and MH after acutely FS on rats, and its possible mechanism. Methods FS rats were treated with CSS, MH, fluoxetine, ghrelin antagonist [D-Lys3]-GHRP-6, and take a series of behavior tests and gastrointestina motility tests, and via 7.0 T fMRI-BOLD signal, compared with well-known mechanism of positive control. Results MH has similar effects to CSS-stimulated deactivation when comparedto those of fluoxetine (4.02-fold for hippocampus and 1.45-fold for thalamus). The ghrelin antagonist [D-Lys3]-GHRP-6 synchronously inhibited A&P and BOLD HTB foci. Prokinetic mosapride had effects on the thalamus and basal ganglia but not the hippocampus. Within the HTB, the hippocampus is implicated in depression and FD. Conclusion These data show that on acute FS-stimulated DB&H, MH-induced rapid A&P, and ghrelin-related regulation coupled to BOLD signals in brain areas before, providing insight into a unified theory of depression pathogenesis and pharmacotherapy.

Development of an Ultra-High Performance Liquid Chromatography Method for Simultaneous Determination of Six Active Compounds in Fructus aurantii and Rat Plasma and Its Application to a Comparative Pharmacokinetic Study in Rats Administered with Different Doses

A rapid, accurate, and sensitive ultra-high performance liquid chromatography (UHPLC) method was established for simultaneously detecting naringin, hesperidin, neohesperidin, meranzin hydrate, naringenin, and hesperetin in Fructus aurantii (FA) decoction. Analysis was performed on Waters BEH (R) C18 (50 mm × 2.1 mm, 1.7 μm) at a flow rate of 0.2 mL/min by using (A) acetonitrile and (B) 0.5% acetic acid-water as the mobile phase. The method was well validated on linearity, precision, recoveries, and stability. Then, we used the same UHPLC conditions for quantitative analysis of meranzin hydrate, naringenin, and hesperetin in rat plasma. The method proved to be linear within the concentration ranges of 3.3–3300 ng/mL for meranzin hydrate, 6.95–3555 ng/mL for naringenin, and 1.8–236 ng/mL for hesperetin. The RSD of precision ranged from 1.22% to 9.08%, and the average extraction recovery ranged from 96.49 ± 1.42% to 102.01 ± 3.16%. Besides, we performed a comparative pharmacokinetic study after oral administration of FA decoction at a low dose of 15 g/kg and high dose of 30 g/kg body weight for seven days to rats. The AUC(0–t) and Cmax of meranzin hydrate, naringenin, and hesperetin were multiplied significantly with the increase of FA dosage, and the t1/2 of meranzin hydrate was faster than naringenin and hesperetin in the two groups.

7-Methoxy-8-Prenylated Coumarins from Murraya koenigii (Linn.) Spreng.

Four coumarin derivatives were isolated from the methanol extract of stem bark of Murraya koenigii (Linn.) Spreng. Extensive spectroscopic studies, including high field NMR analyses allowed to identify these compounds as meranzin hydrate (1), epoxyosthol (2), isomeranzin (3) and murracarpin (4). The identity of the compounds was confirmed by comparison with published data as well as co-TLC with authentic samples. This is the first report of occurrence of meranzin hydrate (1), epoxyosthol (2) and isomeranzin (3) from M. koenigii.Dhaka Univ. J. Pharm. Sci. 15(2): 155-159, 2016 (December)

Coumarins from Murraya exotica Collected in Egypt

Four new coumarins, isomurralonginol senecioate (1), isomurralonginoic acid (2), murrangatin 2′-formate (3), and meranzin hydrate 2′-palmitate (4), were isolated from the vegetative branches of Murraya exotica together with 33 known compounds. The structures of the new compounds were determined from chemical and spectroscopic data.