Isolation of two rare N-glycosides from Ginkgo biloba and their anti-inflammatory activities

Abstract

two rare N-β-D-glucopyranosyl-1H-indole-3-acetic acid conjugates, N-[2-(1-β-D-glucopyranosyl)-1Hindol-3-yl)acetyl]-L-glutamic acid (1) and N-[2-(1-β-D-glucopyranosyl)-1H-indol-3-yl)acetyl]-L-aspartic acid (2) were isolated from Ginkgo biloba. The structures were elucidated by analyses of HRMS and NMR spectroscopic data. In addition, a simplified and efficient synthetic route for compounds 1 and 2 is also disclosed to determine the absolute configurations of them. This concise syntheses of compounds 1 and 2 may facilitate studies of the biology of this type alkaloids. Compounds 1 and 2 were also tested for their cytotoxic and anti-inflammatory activities. The biological evaluation showed that compounds 1 and 2 led to the decrease of interleukin (IL)-6, nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 at mRNA level in lipopolysaccharide (LPS)-stimulated murine macrophage RAW264.7 cells. Ginkgo biloba L., one of the most well-known medicinal plants worldwide, is considered as a living fossil due to its survival over millions of years 1. Pharmacological studies have shown that extracts from its leaves and seeds exhibit antiparasitic, antifungal, antibacterial and antiviral activities. G. biloba extracts have also found broad applications in the treatment of cognitive diseases 2-5. Since the discovery of ginkgolides A-C, a lot of phytochemical and pharmaceutical studies have been conducted on the G. biloba leaves 6-8. It is well known that G. biloba leaf extracts, mainly composed of ginkgolides, flavonoids and phenolic compounds, are frequently used in the treatment of cardiovascular, cerebrovascular, and neurological diseases 9,10. The dried seeds of G. biloba (called "baiguo" in Chinese), have been reported in the Chinese Pharmacopoeia as effective treatments for cough, asthma, enuresis, alcohol misuse, pyogenic skin infections and worm infestations in the intestinal tract 11,12. In contrast to extensive studies on G. biloba leaves, the seeds of G. biloba have received much less attention. In order to find structurally interesting and bioactive components from Ginkgo seeds and provide a better understanding of their functions, we conducted a phytochemical investigation of Ginkgo seeds. As a result, two N-β-D-glucopyranosyl-1H-indole-3-acetic acid conjugates were isolated from the title plant and the concise syntheses of 1 and 2 were also enclosed to determine the absolute configurations of compounds 1 and 2 (Fig. 1). Notably, compounds 1 and 2 are naturally isolated N-glycosides, which are rarely found in natural products. To the best of our knowledge, only very few examples have been reported previouly 13-17. Although compounds 1 and 2 were detected in an alkaline hydrolysate of rice extract using liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) 18 , there are no examples of their isolation, absolute configurations determination and bioactivities. Reported herein are the structural identification, concise syntheses and bioactivities of them. Results and discussion Ginkgos...

N-glucosyltransferase GbNGT1 from ginkgo complements the auxin metabolic pathway

“…IAA-AA- N -glucosides are compounds present in ginkgo seeds that have been confirmed to be pharmacologically active for cough treatment 17 , 18 . NMR showed that these compounds, including IAA-Asp- N -glucoside and IAA-Glu- N -glucoside, were commonly distributed in the mature seeds of 58 ginkgo cultivars or strains (Supplementary Fig.…”

“…Ginkgo flavonoids and ginkgolides have been widely used as important drug and dietary supplements 36 . IAA-Asp- N -glucoside has been discussed as the main pharmacological cough-inhibiting compound in ginkgo and can also be used as an anti-asthmatic and for phlegm elimination 17 , 18 ; furthermore, considerable pharmacological studies on IAA derivates and indole alkaloids have shown IAA-induced cell death in combination with UV-B irradiation to increase apoptosis in PC-3 prostate cancer cells 37 . Indole- N -glucosides have the potential to serve as novel SGLT2-selective inhibitors (sodium-glucose cotransporters) to cure type II diabetes 38 .…”

“…Herein, we found that IAA-Asp- N -glucoside accumulates abundantly in ginkgo seeds ( Ginkgo biloba ); the compound has been reported to inhibit cough 17 , 18 . The content of IAA-Asp- N -glucoside in 58 ginkgo cultivars from China and Japan (two cultivars were introduced from Japan in the 1990s) was 1.02–4.13 mg/g DW higher than that in rice seeds (~0.03 µg/g DW) 19 .…”

Auraptene and umbelliprenin: a review on their latest literature acquisitions

“…Notable and recent examples to this concern are represented by extracts of Gingko biloba L. (Fam. Gingkoaceae) (Cheng et al 2020), of Allium fistulosum L. (Amaryllidaceae) (Zolfaghari et al 2020), of Anneslea fragrans Wall. (Fam.…”

Quantification of 10 bioactive components of Yazhangsan in rat plasma by LC–MS/MS and its application

“…Liquiritin, isoliquiritin, liquiritigenin and isoliquiritigenin (Figure 1) are essential flavonoids in GR (Wu, Meng, Bao, & Wang, 2013). GS is also widely used to treat cough and gynecological diseases (Chinese Pharmacopoeia Commission, 2015), and glucopyranosyl‐1‐ N ‐indole‐3‐acetyl‐ N ‐aspartic acid (IAsp ‐N‐ Glc, Figure 1) is a bioactive component possessing a markable antitussive (Liu, Cheng, Guo, Zhang, & Chen, 2020) and anti‐inflammatory effect (Cheng et al, 2020).…”