Biginkgosides A–I, Unexpected Minor Dimeric Flavonol Diglycosidic Truxinate and Truxillate Esters from Ginkgo biloba Leaves and Their Antineuroinflammatory and Neuroprotective Activities

Abstract

Nine unexpected new flavonol glycoside cyclodimers in the truxinate (1-7, biginkgosides A-G, respectively) or truxillate [biginkgosides H (8) and I (9)] forms were isolated as minor components from the extract of Ginkgo biloba leaves. The new dimers possess an unusual cyclobutane ring formed by a [2+2]-cycloaddition between two symmetric (for compounds 1-5 and 7-9) or nonsymmetric (for 6) flavonol coumaroyl glucorhamnosides. A plausible biosynthetic pathway for these new compounds based on the frontier molecular orbital theory of cycloaddition reactions is briefly discussed. An antineuroinflammatory screening revealed that biginkgosides E (5) and H (8) inhibited nitric oxide production in lipopolysaccharide-activated BV-2 microglial cells, with IC50 values of 2.91 and 17.23 μM, respectively. Additionally, biginkgoside F (6) showed a significant neuroprotective effect (34.3% increase in cell viability at 1 μM) against Aβ25-35-induced cell viability decrease in SH-SY5Y neuroblastoma cells.

Interrogation of spatial metabolome of Ginkgo biloba with high‐resolution matrix‐assisted laser desorption/ionization and laser desorption/ionization mass spectrometry imaging

“…For example, m/z 1,519.3557 (calculated for [C 72 H 72 O 34 + K] + , Δ = 1.34 ppm) was putatively assigned as a dimeric derivative of kaempferol coumaroyl diglycoside (C 36 H 36 O 17 ). In a recent report (Ma et al, ), a new class of flavonoid glycoside cyclodimers, named biginkgosides, were isolated from ginkgo leaf extract, supporting our MALDI MS results. Therefore, m/z 1,519.3557 was tentatively assigned to isomeric biginkgosides ([biginkgoside B/E/I + K] + ), m/z 1,535.3476 assigned to [biginkgoside F + K] + , and m/z 1,551.3435 assigned to the other isomeric biginkgosides also adducted with potassium ([biginkgoside A/C/D/G/H + K] + ; Table S1).…”

“…Significance levels: P < 0.05. The identities of selected flavonoids are summarized in Table S4 flavonoids were only just recently reported (Ma et al, 2016). One possible explanation of their recent discovery and observation here is that rare components with low abundance may not be observed during whole sample homogenization but amendable to MSI because of their localized nature.…”

“…Although the roles of these flavonoid cyclodimers have yet to be determined, the distribution patterns obtained here for the first time may be significant for understanding what biotic factors trigger the production of these unusual dimeric derivatives, their corresponding heterogeneous accumulation patterns, as well as their function in ginkgo leaf development. Investigations of natural products in ginkgo leaf have been performed using effective dereplication strategies for a long time, but these flavonoids were only just recently reported (Ma et al, ). One possible explanation of their recent discovery and observation here is that rare components with low abundance may not be observed during whole sample homogenization but amendable to MSI because of their localized nature.…”

Anti‐inflammatory effects of chemical components from Ginkgo biloba L. male flowers on lipopolysaccharide‐stimulated RAW264.7 macrophages

“…Ginkgo biloba L., the sole species in the class Ginkgopsida, is one of the oldest relict species in the world. This plant is native to China and is currently cultivated worldwide for landscaping and medical purposes (Ma et al, ). The extract of G. biloba leaves (EGb), whose primary active ingredients were identified as flavonol glycosides and terpene trilactones, is one of the top‐selling supplements and medicines derived from natural products (Tian, Liu, & Chen, ) due to its anti‐inflammatory and antioxidant properties (Zhang et al, ), neuroprotection (Zuo, Yan, Zhang, Li, & Mei, ), ability to improve peripheral vascular disorders, and antiplatelet aggregative activity (Tian et al, ).…”

Simultaneous Identification of Characteristic Components in HPLC-PDA-ELSD Fingerprint Profile of Ginkgo biloba Leaves Extract

“…(1-29,Figure 2) from the Sine Promod's EGb product12 ; these 29 compounds included 13 FGs(1, 7, 8, 10, 11, 13-20), 9 FG cyclodimers (21-29), 5 TTLs (3-5, 9, 12), 1 phenolic acid…”