- Regio-selective deglycosylation of icariin by cell suspension cultures of Glycyrrhiza uralensis and Morus alba
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Biotransformations of icariin (1) by cell suspension cultures of Glycyrrhiza uralensis and Morus alba yielded two new metabolites, icaruralins A and B (2 and 3), and one known metabolite, baohuoside I (4). Their structures were determined on the basis of extensive spectroscopic analysis. This is the first report that the cell suspension cultures of G. uralensis and M. alba possess deglycosylation functionality.
- Zhang, De-Wu,Tao, Xiao-Yu,Chen, Ri-Dao,Yu, Li-Yan,Dai, Jun-Gui
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- Exploring the catalytic promiscuity of a new glycosyltransferase from Carthamus tinctorius
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The catalytic promiscuity of a new glycosyltransferase (UGT73AE1) from Carthamus tinctorius was explored. UGT73AE1 showed the capability to glucosylate a total of 19 structurally diverse types of acceptors and to generate O-, S-, and N-glycosides, making it the first reported trifunctional plant glycosyltransferase. The catalytic reversibility and regioselectivity were observed and modeled in a one-pot reaction transferring a glucose moiety from icariin to emodin. These findings demonstrate the potential versatility of UGT73AE1 in the glycosylation of bioactive natural products.
- Xie, Kebo,Ridao, Chen,Li, Jianhua,Wang, Ruishan,Chen, Dawei,Dou, Xiaoxiang,Dai, Jungui
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- Characterization of a novel thermostable glucose-tolerant GH1 β-glucosidase from the hyperthermophile Ignisphaera aggregans and its application in the efficient production of baohuoside I from icariin and total epimedium flavonoids
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The minor flavonoid baohuoside I from Herba epimedii has better bioactivities than its precursor compounds icariin and other major epimedium flavonoids. In this study, a novel β-glucosidase gene (Igag_0940) was cloned and expressed to improve the conversion efficiency in the process of baohuoside I production. For the first time, the recombinant IagBgl1 was purified and then identified uniquely as a trimer in GH 1 family protein from Archaea. The maximum activity of recombinant IagBgl1 was exhibited at 95 °C, pH 6.5, and it retained more than 70% after incubation at 90 °C for 4 h. IagBgl1 had a high catalytic activity towards icariin with a Kcat/Km ratio of 488.19 mM?1·s?1. Under optimized conditions (65 °C, pH 6.5, 0.8 U/mL enzyme, and 90 min), 10 g/L icariin was transformed into 7.564 g/L baohuoside I with a molar conversion of 99.48%. Meanwhile, 2.434 g/L baohuoside I was obtained from 10 g/L total epimedium flavonoids by a two-step conversion system built with IagBgl1 and two other thermostable enzymes. This is the first report of enzymatic conversion for producing baohuoside I by thermostable enzymes.
- Jiang, Jianchun,Wei, Min,Xie, Jingcong,Xu, Hao,Yang, Jing,Zhang, Ning,Zhao, Jian
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- Exploration of icariin analog structure space reveals key features driving potent inhibition of human phosphodiesterase-5
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The natural product icariin inhibits human phosphodiesterase-5 (PDE5) and represents a unique pharmacophore for treating erectile dysfunction, pulmonary hypertension, and other diseases. In this study, we explore the available icariin-derived chemical scaffolds through medicinal chemistry to develop novel icariin PDE5 inhibitors with improved potency and specificity. We synthesized six novel semi-synthetic icariin analogs as well as three naturally occurring icariin analogs, and characterized the structure-activity relationship in the context of human PDE5 inhibition using in vitro enzyme inhibition and kinetics assays and molecular modeling. Mammalian-cell-based assays and in vitro enzyme inhibition assays against human PDE6C further helped to identify the most potent and selective icariin analogs. Our results reveal the synergistic contribution of functional groups at the C3 and C7 positions of the icariin backbone towards PDE5 inhibition. Whereas a hydrophobic and flexible alkanol group at the C7 position is sufficient to enhance icariin analog potency, combining this group with a hydrophilic sugar group at the C3 position leads to further enhancement of potency and promotes specificity towards PDE5 versus PDE6C. In particular, compounds 3 and 7 exhibit Ki values of 0.036 ± 0.005 μM and 0.036 ± 0.007 μM towards PDE5 respectively, which are approaching those of commercial PDE5 inhibitors, and can effectively reduce GMP levels in cultured human BJ-hTERT cells. This study identifies novel icariin analogs as potent and selective PDE5 inhibitors poised to become lead compounds for further pharmaceutical development.
- Chau, Yasmin,Li, Fu-Shuang,Levsh, Olesya,Weng, Jing-Ke
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- Baohuoside i production through enzyme hydrolysis and parameter optimization by using response surface and subset selection
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A rapid and efficient baohuoside I preparation method was established. A uniform design coupled with subset selection was employed to determine pH, reaction time, and temperature parameters, as well as dextranase hydrolysis efficiency. Hydrolysis parameters were optimized using response surface and subset selection. Our results showed that pH plays an important role in the hydrolysis reaction within a relatively narrow range (pH 4-7). Temperature was the secondary factor, which was positively correlated with conversion rate. A 3-h reaction time was sufficient. Finally, a relatively good hydrolysis parameters were found, and their effectiveness was verified.
- Yang, Qianxu,Wang, Li,Zhang, Liangxiao,Xiao, Hongbin
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- A regiospecific rhamnosyltransferase from: Epimedium pseudowushanense catalyzes the 3- O -rhamnosylation of prenylflavonols
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Epimedium is used in traditional Chinese medicine and contains flavonol glycosides that exhibit multiple biological activities. These bioactive flavonol glycosides usually have a rhamnose moiety at the 3-OH position of prenylflavonols, such as icariin (9), baohuoside I (1a) and baohuoside II (2a). However, to date, no rhamnosyltransferase has been reported to catalyze the 3-O-rhamnosylation of prenylflavonols. In this article, a flavonol rhamnosyltransferase, EpPF3RT, was identified from E. pseudowushanense B. L. Guo. The recombinant enzyme regiospecifically transfers a rhamnose moiety to 8-prenylkaempferol (1) and anhydroicaritin (2) at the 3-OH position to form baohuoside II (1a) and baohuoside I (2a) in vitro. In addition, a UDP-rhamnose synthase gene, EpRhS, from E. pseudowushanense was functionally characterized and used to produce the UDP-rhamnose sugar donor. Furthermore, an engineered Escherichia coli strain containing EpPF3RT and EpRhS was established to produce baohuoside II (1a) from whole cells. These studies indicate the significant potential of an enzymatic approach for the rhamnosylation of bioactive flavonoids in Epimedium plants and will provide a promising alternative for producing bioactive rhamnosylated flavonoids combined with other genes/enzymes by synthetic biology.
- Feng, Keping,Chen, Ridao,Xie, Kebo,Chen, Dawei,Guo, Baolin,Liu, Xiao,Liu, Jimei,Zhang, Min,Dai, Jungui
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- Biotransformation of major flavonoid glycosides in herb epimedii by the fungus Cunninghamella blakesleana
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Biotransformation of icariin (1), epimedin C (2), epimedoside A (3), epimedin A (4) and epimidin B (5), five major components of E. koreanum, were performed by using Cunninghamella blakesleana. And they could be metabolized efficiently to icariside II (1a), 2″-O-rhamnosylikarisoside II (2a), epimedoside b (3a), baohuoside VII (4a) and sagittatoside B (5a) with high yields of 95.1%, 97.7%, 93.7%, 95.8% and 96.4%, respectively. And these transformed products as major forms of herb epimedii in vivo exhibited the more significant anti-osteoporosis activities. Our method could be applied for enriching these rare flavonoids in herb epimedii, for further development of anti-osteoporosis medicines or functional foods.
- Xin, XiuLan,Fan, Guang-Jun,Sun, Zheng,Zhang, Ning,Li, Ye,Lan, Rong,Chen, Liang,Dong, PeiPei
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- Preparation of icariside II from icariin by enzymatic hydrolysis method
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It has been reported that icariin and icariside II, two flavonoid glycosides coming from herba epimedii,which have a closely structural relationship, showsome pharmacological effects such as preventing osteoporosis, cancer and depression. The content of natural icariside II is very low in herba epimedii, but it is the main component in vivo after the administration of herba epimedii. More icariside II can be obtained from icariin by enzymatic hydrolysis method than by traditional isolationmethod. This study focuses on finding a simple and feasiblemethod to prepare icariside II from icariin by enzymatic hydrolysis, so as to meet the request for further pharmacologic actions study. Icariin was obtained successively with 90% ethanol extraction, isolation on macroporous resin and purification on silica gel chromatography. Enzymatic hydrolysis conditions were tested for the bioconversion of icariin into icariside II by orthogonal array design. The structures of isolated icariin and produced icariside II were identified by UV, IR, ESIMS, 1H NMR, 13C NMR, and DEPT spectroscope. Enzymatic hydrolysis experiment showed that icariin could be transformed into icariside IIwith the action of β-glucosidase and the optimumreaction conditionswere determined as follows: 50 °C, 0.2 M disodium hydrogen phosphate and citric acid buffer system (pH6.0), the ratio of icariin/enzyme is 1:1 and reaction time 5 h. By using this enzymatic condition, 95.5 mg icariside II (with the purity of 99.1%) was obtained eventually by transforming 200 mg icariin.
- Xia, Quan,Xu, Dujuan,Huang, Zhaogang,Liu, Jianjun,Wang, Xinqun,Wang, Xiu,Liu, Shangquan
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- ANALOGS OF THE NATURAL PRODUCT ICARIIN
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Provided herein are analogs of the natural product icariin represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof. The analogs can be used to modulate (e.g., inhibit, such as by competitive inhibition) PDE5 and thereby treat a wide range of PDE5- mediated diseases, including cardiovascular, gastrointestinal, pulmonary, musculoskeletal, neurological and reproductive diseases. Also provided herein are compositions and methods including compounds of Structural Formula (I).
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Paragraph 00168; 00182
(2020/03/02)
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- Ep7GT, a glycosyltransferase with sugar donor flexibility from: Epimedium pseudowushanense, catalyzes the 7- O -glycosylation of baohuoside
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Icariin (1a), a 7-O-glycosylated flavonoid glycoside, is recognized as the major pharmacologically active ingredient of Epimedium plants, which have been used in traditional Chinese medicine for thousands of years. However, no glycosyltransferase (GT) responsible for the 7-O-glycosylation of flavonoids has been identified from Epimedium plants to date. Herein, a GT, Ep7GT, was identified from E. pseudowushanense B. L. Guo, which can regiospecifically transfer a glucose moiety to baohuoside (1) at 7-OH to form icariin (1a). Ep7GT showed a rare broad donor substrate spectrum, including UDP-glucose, UDP-xylose, UDP-N-acetylglucosamine, UDP-rhamnose, UDP-galactose, UDP-glucuronic acid and TDP-glucose. Moreover, two new derivatives of icariin (1a), 7-O-β-d-[2-(acetylamino)-2-deoxy-glucopyranosyl]-baohuoside (1b) and 7-O-β-d-xylosyl-baohuoside (1c), were biosynthesized by using Ep7GT in vitro. Engineered Escherichia coli harbouring Ep7GT was constructed, and 10.1 μg mL-1 icariin (1a) was yielded by whole-cell biotransformation with baohuoside (1) as the substrate. The present work not only characterizes the GT responsible for the 7-O-glycosylation in the biosynthesis of icariin in Epimedium plants, but also indicates the significant potential of an enzymatic approach for the production of glycosylated baohuoside derivatives with different sugar moieties. What's more, these findings also provide a promising alternative for producing natural/unnatural bioactive flavonoid glycosides by metabolic engineering.
- Feng, Keping,Chen, Ridao,Xie, Kebo,Chen, Dawei,Liu, Jimei,Du, Wenyu,Yang, Lin,Dai, Jungui
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supporting information
p. 8106 - 8114
(2019/09/19)
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- Herba Epimedii glycoside compound and use thereof
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The invention relates to an icariin compound and an application of the icariin compound in preparing medicines for preventing and treating fracture and osteoporosis. Particularly, the invention relates to the compound shown in a general formula (I) in the specification, a stereisomer, a stereomer, a tautomer, oxynitrides, hydrates, solvates, metabolites, and pharmaceutically acceptable salts or prodrugs thereof, wherein the variables are defined in the specification. The invention further relates to use of the compound, the stereisomer, the stereomer, the tautomer, oxynitrides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or salt of prodrugs thereof as medicines, particularly use in preparing medicines for preventing and treating fracture and osteoporosis.
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Paragraph 0167; 0168; 0169; 0170; 0171
(2017/08/24)
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- Herba Epimedii glycoside compound and use thereof
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The invention relates to a kind of icariin compounds shown in a formula (I) or stereoisomers, geometrical isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of the compounds shown in the formula (I). The invention also discloses a drug composition containing the compounds, a preparation method of the compounds or the drug composition and an application of the compounds or the drug composition to inhibiting the activity of phosphoesterase, promoting development of gonads and preventing and treating sexual dysfunction.
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Paragraph 0109; 0110; 0111; 0112
(2017/08/14)
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- A kind of icariin derivatives and their methods of use and use (by machine translation)
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The invention provides an icariin derivative as shown in formula (I) or a stereisomer, a tautomer, nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, and a pharmaceutical composition. The invention further relates to a method for preparing the compounds and the pharmaceutical composition, and a use thereof in prevention or treatment of sexual dysfunction, cardiac-cerebral vascular diseases, osteoporosis or cancers. The formula is described in the description.
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Paragraph 0156-0159
(2016/12/07)
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- Heiba boschnaloside compound and use thereof
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The invention relates to a kind of icariin compounds shown in a formula (I) or stereoisomers, geometrical isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of the compounds shown in the formula (I). The invention also discloses a drug composition containing the compounds, a preparation method of the compounds or the drug composition and an application of the compounds or the drug composition to preparation of drugs for preventing and treating fractures and osteoporosis.
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Paragraph 0118-0121
(2020/02/08)
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- Potent inhibition of human phosphodiesterase-5 by icariin derivatives
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Plant extracts traditionally used for male impotence (Tribulus terrestris, Ferula hermonis, Epimedium brevicornum, Cinnamomum cassia), and the individual compounds cinnamaldehyde, ferutinin, and icariin, were screened against phosphodiesterase-5A1 (PDE5A1) activity. Human recombinant PDE5A1 was used as the enzyme source. Only E. brevicornum extract (80% inhibition at 50 μg/mL) and its active principle icariin (1) (IC50 5.9 μM) were active. To improve its inhibitory activity, 1 was subjected to various structural modifications. Thus, 3,7-bis(2-hydroxyethyl)icaritin (5), where both sugars in 1 were replaced with hydroxyethyl residues, potently inhibited PDE5A1 with an IC50 very close to that of sildenafil (IC50 75 vs 74 nM). Thus, 5 was 80 times more potent than 1, and its selectivity versus phosphodiesterase-6 (PDE6) and cyclic adenosine monophosphate-phosphodiesterase (cAMP-PDE) was much higher in comparison with sildenafil. The improved pharmacodynamic profile and lack of cytotoxicity on human fibroblasts make compound 5 a promising candidate for further development.
- Dell'Agli, Mario,Galli, Germana V.,Dal Cero, Esther,Belluti, Federica,Matera, Riccardo,Zironi, Elisa,Pagliuca, Giampiero,Bosisio, Enrica
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experimental part
p. 1513 - 1517
(2009/09/29)
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- COSMETIC COMPOSITION CONTAINING HYDROLYSATES OF ICARIIN
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The present invention relates to a cosmetic composition containing hydrolysates of icariin, and more particularly, a cosmetic composition containing hydrolysates of icariin including icaritin, icariside I and icariside II. The hydrolysates of icariin is prepared by a method comprising the steps of: (a) obtaining an extract from a plant containing icariin using water or an organic solvent; and (b) hydrolyzing the plant extract with an acid, a base, an enzyme or a microorganism producing the enzyme. The cosmetic composition according to the present invention is employed for anti-oxidant, anti-aging, whitening or anti-wrinkling effects.
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Page/Page column 12-13
(2008/06/13)
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