黑蕊虎耳草中岩白菜素没食子酸酯类及其对丙型肝炎丝氨酸蛋白酶的抑制作用

研究了黑蕊虎耳草(Saxifraga melanocentra)中岩白菜素衍生物的化学和生物活性,从其地上部分分离纯化得到一个新的岩白菜素没食子酸酯,主要通过1维和2维核磁共振波谱鉴定结构为11-氧-(4-氧甲基没食子酰)岩白菜素[11-O-(4-O-methylgalloyl) bergenin(1)] ,该化合物对丙型肝炎丝氨酸蛋白酶(HCVNS3serine protease)具有抑制活性,其IC50为0.32 mg/mL。     

Determination of bergenin based on the electrochemiluminescence quenching of tris(2,2′‐bipyridine)‐ruthenium(II)

Quenching effects of bergenin, based on the electrochemiluminescence (ECL) of the tris(2,2′‐bipyridyl)‐ruthenium(II) (Ru(bpy)₃²⁺)/tri‐n‐propylamine (TPrA) system in aqueous solution, is been described. The quenching behavior can be observed with a 100‐fold excess of bergenin over Ru(bpy)₃²⁺. In the presence of 0.1 m TPrA, the Stern–Volmer constant (K_SV) of the ECL quenching is as high as 1.16 × 10⁴ M^?1 for bergenin. The logarithmic plot of the inhibited ECL versus logarithmic plot of the concentration of bergenin was linear over the range 3.0 × 10^?6–1.0 × 10^?4 mol/L. The corresponding limit of detection was 6.0 × 10^?7 mol/L for bergenin (S/N = 3). In the mechanism of quenching it is believed that the competition of the active free radicals between Ru(bpy)₃²⁺/TPrA and bergenin was the key factor for the ECL inhibition of the system. Photoluminescence, cyclic voltammetry, coupled with bulk electrolysis, supports the supposition mechanism of the Ru(bpy)₃²⁺/TPrA–bergenin system. Copyright © 2015 John Wiley & Sons, Ltd.     

Bergenin: a computationally proven promising scaffold for novel galectin-3 inhibitors

Bergenin is a C-glycoside of 4-O-methylgallic acid that is isolated from medicinal plants such as Flueggea leucopyrus, Bergenia crassifolia, Mallotus philippensis, Corylopsis spicata, Caesalpinia digyna, Mallotus japonicus, and Sacoglottis gabonensis. Even though there appears to be ample evidence from South Asian traditional medicine that bergenin possesses strong anticancer activity, no comprehensive scientific study has been carried out to test its anticancer potency. Therefore, in this study, the potential mechanisms of action for bergenin’s postulated anticancer activity were examined using computational techniques. Firstly, bergenin was tested for its toxicity as a drug candidate using in silico toxicity analysis. It was found that bergenin is nontoxic according to modern toxicity measures. The optimized structure of bergenin was obtained at the DFT-B3LYP/6-31G(d) level of theory. Potential biological targets of bergenin were identified using reverse docking calculations. Reverse docking results suggested that galectin-3 is a potential target of bergenin. Gelectin-3 is an enzyme that plays a major role in cell–cell adhesion, cell-matrix interactions, macrophage activation, angiogenesis, metastasis, and apoptosis in cancer, making it a popular target in anticancer drug design. Among the many potential biological targets predicted by reverse docking calculations, galectin-3 was selected as it complies with the primary objective of this study. The binding of bergenin to galectin-3 was studied by conventional forward docking calculations. Classical molecular dynamics (MD) simulations were used to study the stability of the galectin-3:bergenin complex. Docking calculations indicated that bergenin has the potential to effectively bind to the carbohydrate recognition domain (CRD) of galectin-3. As well as electrostatic and van der Waals interactions, a few strong hydrogen bonds were found to be involved in the binding of bergenin to galectin-3. There is also a plausible π-stacking interaction between the aromatic moiety of bergenin and the His158 residue at the binding site. A 50-ns MD simulation was carried out for the bergenin:galectin-3 complex in a cubic water box with periodic boundary conditions. The MD results showed that the bergenin:galectin-3 complex is highly stable and confirmed the veracity of the docking results, which suggested that bergenin potentially exerts an inhibitory effect on galectin-3. This study therefore sheds new light on the anticancer activity of bergenin and demonstrates that bergenin could potentially be used to develop more potent galectin-3 inhibitors. The study also provides scientific evidence supporting the use of bergenin-containing plants in cancer treatments in Eastern traditional medicine.

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Graphical abstract Bergenin in the galectin-3 binding site

     

Structure-activity relationships of bergenin derivatives effect on α-glucosidase inhibition

The α-glucosidase inhibitory activities of bergenin derivatives were evaluated. Bergenin derivatives were synthesized from bergenin which is a characteristic compound of B. ligulata. A new bergenin derivative, 11-O-(3′,4′-dimethoxybenzoyl)-bergenin showed the highest potent inhibitory activity among those of bergenin derivatives. The presence of substituents at 3′,4′-position in bergenin derivatives altered the α-glucosidase inhibitory activity. 11-O-(3′,4′-dimethoxybenzoyl)-bergenin was noncompetitive inhibitor for α-glucosidase. The present study reveals that bergenin derivatives could be classified as a new group of α-glucosidase inhibitors.     

Studies onC-glycosides in higher plants

Sixteen species including 1 variety and 1 form from 9 genera belonging to Saxifragaceae were examined for bergenin content. Bergenin was found only in Saxifragoideae, no bergenin being present in Hydrangeoideae and Ribesioideae. The amount of bergenin was shown to range from 0.1 to 1 mg per g fresh weight, depending on the organs tested, and the highest amounts were usually observed in rhizomes. The contents of bergenin in a leaf ofSaxifraga stolonifera increased continuously with the leaf expansion, while the level on a fresh weight basis remained constant during the leaf growth.     

Bergenin glycosides from Rodgersia aesculifolia

Phytochemical investigation on Rodgersia aesculifolia afforded twenty-three compounds, including three bergenin glycosides, previously unknown in nature, together with twenty known compounds. Their structures were elucidated by the extensive use of 1D and 2D NMR experiments, along with IR and HRESIMS spectra. This is the first report of bergenin glycosides from nature.     

Studies onC-glycosides in higher plants

The biosynthesis of bergenin and arbutin in the organs ofSaxifraga stolonifera has been studied by tracer techniques. Among the organs tested, the leaves showed the highest incorporation of label fromd-glucose-U-¹⁴C into bergenin and arbutin under continuous light, although every organ is more or less able to synthesize both glucosides. The incorporation rate into bergenin was higher in the young leaves, whereas the synthesis of arbutin became active in the mature leaves. The fact that the addition of unlabeled gallic acid enhanced the incorporation of label into bergenin suggests that gallic acid may be a likely glucosyl acceptor in bergenin biosynthesis.     

朱砂根愈伤组织诱导及其岩白菜素含量的测定

取朱砂根(Ardisia crenota Sims．)幼苗不同部位作外植体,研究不同激素组合对愈伤组织诱导的影响,利用薄层层析(TLC)和高效液相色谱(HPLC)检测愈伤组织中岩白菜素含量。实验结果表明朱砂根幼苗的不同部位(胚根、下胚轴、茎及叶)均能诱导出愈伤组织,最高诱导率都在45％以上,以MS基本培养基添加2,4—D0．5mg L^-1和KT0．01mg L^-1时愈伤组织的诱导和生长最好。这些愈伤组织均有合成岩白菜素的能力,其中以胚根诱导的愈伤组织中岩白菜素含量最高,为干重的0．076％,相当于原植物根中含量的1／9。高效液相色谱定量测定法精密度高,专一性好,能准确检测朱砂根愈伤组织中岩白菜素的含量。     

Microbial Degradation of Bergenia,a Phenolic C-Glucoside

A strain of soil bacteria was isolated by elective culture with bergenia, a C-glucoside having dihydroisocoumarin structure, as a sole carbon source, and was identified as Erwinia herbicola. In growth or replacement medium, the bacterium degraded bergenin to yield at least two major degradation products, one of them being identified as 4-O-methylgallic acid (compound I), an aglycone of bergenin. The bacterium seemed to utilize the sugar moiety of bergenin preferentially as carbon and energy sources, since the rate of further transformation of compound I by the bacterium was slow. In replacement culture with compound I, gallic acid was detected as one of the metabolites. A possible pathway for microbial degradation of bergenin is proposed.     

厚叶算盘子的化学成分研究(Ⅱ)

从厚叶算盘子(Glochidion hirsutum)的乙醇提取物中,用硅胶和凝胶柱层析分离得到8个化合物,通过波谱学方法鉴定为bergenin(1),isovitexin(2),isovitexin 7-O-xyloside(3),decoumaroylibotanolide(4),n-butyl-α-D-fructofuranoside(5),n-butyl-β-D-fructofuranoside(6),4-O-ethylgallic acid(7),3-O-methylgallic acid(8)。以上化合物均为首次从该植物中分离得到。     

Occurrence of bergenin phenylpropanoates in Vatica bantamensis

We isolated five bergenin phenylpropanoates, i.e., 11-O-(E)-sinapate (1), 11-O-(E)-ferulate (2), 11-O-(Z)-ferulate (3), 11-O-(E)-coumalate (4), and 11-O-(Z)-coumalate (5), and three bergenin hydroxybenzoates, i.e., 11-O-syringate (6), 11-O-vanillate (7), and 11-O-p-hydroxybenzoate (8), along with bergenin (9), from the leaves of Vatica bantamensis. Moreover, we identified the geometrical isomerization between 2 and 3. These structures were characterized by nuclear magnetic resonance (NMR). This is the first report that shows the occurrence of bergenin phenolic acid esters in dipterocarpaceaeous plants.     

Synthesis of new bergenin derivatives as potent inhibitors of inflammatory mediators NO and TNF-α

Bergenin is an isocoumarin natural product which aides in fat loss, healthy weight maintenance, enhancing the lipolytic effects of norepinephrine, inhibiting the formation of interleukin 1α and cyclooxygenases-2. Here we describe the anti-inflammatory activity of new bergenin derivatives 1-15 in the respiratory burst assay. Bergenin was isolated from the crude extract of Mallotus philippenensis after repeated column chromatography and was then subjected to chemical derivatization. The structures of all compounds were elucidated by NMR and mass spectroscopic techniques. Compound 2 was also studied using single crystal X-ray diffraction. Compounds 4, (54.5±2.2%) 5 (47.5±0.5%) 5, and 15 (86.8±1.9%) showed significant (P≤0.005) NO inhibitory activities whereas 6, 7, 11, 12 and 13 displayed moderate inhibitory activities that ranges between 16% and 31%. Furthermore compounds 4 and 15, were discovered as significant (P≤0.005) TNF-α inhibitors with 98% and 96% inhibition, respectively, while compounds 3, 5, 7, 8, 11, and 12 showed low level of TNF-α inhibition (0.4-28%). Compounds 8, 13 and 15 exhibited moderate anti-inflammatory IC(50) activities with 212, 222, and 253 μM, respectively, compared to the standard anti-inflammatory drug indomethacin as well as the parent bergenin compound. No cytotoxic effects could be detected when the compounds were tested on 3T3 cells up to concentrations of 100 μM.     

Chemical constituents and antioxidant activity of Mallotus roxburghianus leaves

Mallotus roxburghianus is used in the traditional medicine in North-Eastern India, but previously no work has been done on the identification of bioactive compounds. Two new compounds, 3-(1-C-beta-D-glucopyranosyl)-2,6-dihydroxy-5-methoxybenzoic acid (6) and 2,4,8,9,10-pentahydroxy-3,7-dimethoxyanthracene-6-O-beta-D-rhamnopyranoside (7) together with beta-sitosterol (1), stigmasterol (2), betulinic acid (3), 4-hydroxybenzoic acid (4), beta-sitosterol-beta-D-glucoside (5), and bergenin (8) were isolated and identified from the leaves of M. roxburghianus. The chloroform soluble portion of the alcoholic extract of leaf, and compounds 3, 6, 7, and 8 exhibited encouraging antioxidant activities.     

Studies onC-glycosides in higher plants

The intracellular distribution of bergenin and related compounds was examined in mesophyll cell protoplasts ofSaxifraga stolonifera. Vacuoles ofS. stolonifera leaves contained 46% to 55% of the bergenin and related compounds. It was also noted that 50% of the gallic acid was located in chloroplasts. From the results obtained it was concluded that bergenin and norbergenin were primarily localized in the vacuoles, but gallic acid was distributed equally in vacuoles and chloroplasts.     

Synthesis and biological evaluation of bergenin-1,2,3-triazole hybrids as novel class of anti-mitotic agents

In continuation of our investigation of pharmacologically-motivated natural products, we have isolated bergenin (1) as a major compound from Mallotus philippensis, which is deployed in different Indian traditional systems of medicine. Here, a series of bergenin-1,2,3-triazole hybrids were synthesized and evaluated for their potentials against a panel of cancer cell lines. Several of the hybrid derivatives were found more potent in comparison to parent compound bergenin (1). Among them, 4j demonstrated potent activity against A-549 and HeLa cell lines with IC₅₀ values of 1.86 µM and 1.33 μM, respectively, and was equipotent to doxorubicin. Cell cycle analysis showed that 4j arrested HeLa cells at G2/M phase and lead to accumulation of Cyclin B1 protein. Cell based tubulin polymerization assays and docking studies demonstrated that 4j disrupts tubulin assembly by occupying colchicine binding pocket of tubulin.     

Synthesis and antiglycation potentials of bergenin derivatives

Bergenin (1), major bioactive compound isolated from methanolic extract of Mallotus philippinensis, displayed moderate AGE inhibition activity (IC₅₀ = 186.73 μM). A series of derivatives of bergenin (3a-k) containing variety of aromatic acids were synthesized under mild conditions by modification of sugar part. Selective esterification of hydroxyl groups on the sugar part enhanced antiglycation potential of bergenin. Compounds 3j and 3k exhibited potent antiglycation activity with the IC₅₀ values of 60.75 and 12.28 μM, respectively.     

Acetophenone and stilbene derivatives from Gnetum ula

The isolation of bergenin, 2-hydroxy-4-benzyloxyacetophenone and the related dimer and stilbene from Gnetum ula is reported.     

虎耳草不同光温条件下光合特性及有效成分含量的相关性分析

对盆栽的虎耳草进行不同光照和温度处理,测定其叶片光合特性及重要有效成分,分析虎耳草有效成分与光合速率的相关性。结果表明：虎耳草光合速率在透光率50%的条件下最高,透光率100%下最低;100%光照下的岩白菜素和没食子酸的含量最高。光合速率在20℃/16℃（12 h昼/12 h夜）适温下最高,此时岩白菜素和没食子酸的含量也最高。相关性分析表明,温度处理条件下的岩白菜素和没食子酸含量与光合速率、气孔张开面积等呈正相关,其中没食子酸含量与光合速率及蒸腾速率的正相关达极显著;不同光照条件下,没食子酸含量与光合有效辐射呈显著正相关。