- Reaction coupling separation for isosteviol production from stevioside catalyzed by acidic ion-exchange resin
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Abstract: Isosteviol, a prodrug used to be obtained via Wagner–Meerwein rearrangement from steviol with low yield and long reaction?time. Herein, an in-situ separation-coupling-reaction is presented to prepare isosteviol from the natural sweetener stevioside. Simply with in-situ water-washing, the product containing 92.98% purity of isosteviol was obtained with a stevioside conversion of 97.23% from a packet bed reactor without further separation. Within the assayed inorganic acid, organic acids and acidic ionic liquids, the acidic ion-exchange resins provided higher product specificity towards isosteviol. Furthermore, comparing to 5-Fluorouracil, the product presented similar and even stronger inhibition on proliferation of the assayed human cancer cells in a time and dose-dependence by causing cell phase arrest. Isosteviol treatment caused G1 arrest on SGC-7901, HCT-8 and HCT-116 cells, S arrest on HepG2, Huh-7 and HepG3B cells, and G2 arrest on MGC-803 cells, respectively. Graphic abstract: Reaction coupling separation for isosteviol production catalyzed by acidic ion-exchange resin.[Figure not available: see fulltext.]
- Hu, Xueyi,Zhou, Zhuoyu,Zhang, Zongying,Wang, Xiaoxia,Sui, Xiaochen,Chen, Junming,Xia, Yongmei,Zhang, Jue,Lin, Jianguo
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- (-)-isosteviol as a versatile ex-chiral-pool building block for organic chemistry
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(-)-Isosteviol is readily available in large quantities by the acidic treatment of a common alternative sweetener. The two functional groups of (-)-isosteviol are presented on the same side of the ent-beyerane scaffold with a mutual C-C distance of about
- Lohoelter, Christina,Weckbecker, Magdalena,Waldvogel, Siegfried R.
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- Synthesis, Structure, and Cytotoxic Activities of a Novel Lactam of the Diterpenoid Isosteviol
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A novel compound lactam of 15β-hydroxymethylisosteviol ethyl ester 3 has been synthesized and structurally characterized by IR, NMR, and HR-MS. Its X-ray crystallographic analysis revealed that the nitrogen is attached to C-13 instead of C-15. The reaction mechanism was discussed, and the title compound was further evaluated against HCT-116, HGC-27, and JEKO-1 cells by the MTT assay. The results demonstrated that compound 3 exhibited better cytotoxic activities than its corresponding precursor isosteviol.
- Liu, Cong-Jun,Li, Jing-Jing,Min, Yu-Tao,Zhang, Ling-Li,Wang, Bao-Yu,Wang, Ya-Hao
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- Structural analysis of isosteviol and related compounds as DNA polymerase and DNA topoisomerase inhibitors
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Isosteviol (ent-16-ketobeyeran-19-oic acid) is a hydrolysis product of stevioside, which is a natural sweetener produced in the leaves of Stevia rebaudiana (Bertoni) Bertoni. In this report, we prepared isosteviol and related compounds from stevioside by microbial transformation and chemical conversion and assayed the inhibitory activities toward DNA metabolic enzymes and human cancer cell growth. Among twelve compounds obtained, only isosteviol (compound 3) potently inhibited both mammalian DNA polymerases (pols) and human DNA topoisomerase II (topo II), and IC50 value for pol α was 64.0 μM. This compound had no inhibitory effect on higher plant (cauliflower) pols, prokaryotic pols, human topo I, and DNA metabolic enzymes such as human telomerase, T7 RNA polymerase, and bovine deoxyribonuclease I. With pol α, isosteviol acted non-competitively with the DNA template-primer and nucleotide substrate. Isosteviol prevented the growth of human cancer cells, with LD 50 values of 84-167 μM, and 500 μg of the compound caused a marked reduction in TPA (12-O-tetradecanoylphorbol-13-acetate)-induced inflammation (inhibitory effect, 53.0%). The relationship between the structure of stevioside-based compounds and these activities were discussed.
- Mizushina, Yoshiyuki,Akihisa, Toshihiro,Ukiya, Motohiko,Hamasaki, Yusuke,Murakami-Nakai, Chikako,Kuriyama, Isoko,Takeuchi, Toshifumi,Sugawara, Fumio,Yoshida, Hiromi
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- Synthesis and anti-hepatitis B virus activity of C4 amide-substituted isosteviol derivatives
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A series of novel isosteviol derivatives having C4-amide substituents were synthesized in order to test for antiviral effects against the hepatitis B virus (HBV) in vitro. Among them, IN-4 [N-(propylcarbonyl)-4α-amino-19-nor-ent-16-ketobeyeran] (5) exhibited inhibitory activity against secretion of HBsAg and HBeAg as well as inhibition of HBV DNA replication. Therefore, the mechanism of its antiviral activity was further analyzed using HBV-transfected Huh7 cells. Exposure to IN-4 produced minimal inhibitory effects on viral precore/pregenomic RNA expression. However, expression levels of the 2.4/2.1-kb preS/major S RNA of the viral surface gene significantly decreased, along with intracellular levels of HBV DNA. A promoter activity analysis demonstrated that IN-4 significantly inhibited viral X, S, and preS expression levels but not viral core promoter activities. In particular, IN-4 was observed to significantly inhibit HBV gene regulation by disrupting nuclear factor (NF)-κB-associated promoter activity. In addition, the nuclear expression of p65/p50 NF-κB member proteins was attenuated following IN-4 treatment, while cytoplasmic IκBα protein levels were enhanced. Meanwhile, IN-4 was observed to inhibit the binding activity of NF-κB to putative DNA elements. Furthermore, transfection of a p65 expression plasmid into Huh7 cells significantly reversed the inhibitory effect of IN-4 on HBV DNA levels, providing further evidence of the central role of NF-κB in its antiviral mechanism. It is therefore suggested that IN-4 inhibits HBV by interfering with the NF-κB signaling pathway, resulting in downregulation of viral gene expression and DNA replication.
- Huang, Tsurng-Juhn,Yang, Cheng-Lin,Kuo, Yu-Cheng,Chang, Yi-Chih,Yang, Li-Ming,Chou, Bo-Hon,Lin, Shwu-Jiuan
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- Endothelium-independent vasorelaxation effects of 16-O-acetyldihydroisosteviol on isolated rat thoracic aorta
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Aims: The aim of this study is to investigate the vasorelaxant effect of 16-O-acetyldihydroisosteviol (ADIS) and its underlying mechanisms in isolated rat aorta. Main methods: Rat aortic rings were isolated, suspended in organ baths containing Kreb's solution, maintained at 37°C, and mounted on tungsten wire and continuously bubbled with a mixture of 95% O2 and 5% CO2 under a resting tension of 1 g. The vasorelaxant effects of ADIS were investigated by means of isometric tension recording experiment. Key findings: ADIS (0.1 μM-3 mM) induced relaxation of aortic rings pre-contracted by phenylephrine (PE, 10 μM) and KCl (80 mM) with intact-endothelium (Emax = 79.26 ± 3.74 and 79.88 ± 3.79, respectively) or denuded-endothelium (Emax = 88.05 ± 3.69 and 78.22 ± 6.86, respectively). In depolarization Ca2+-free solution, ADIS inhibits calcium chloride (CaCl2)-induced contraction in endothelium-denuded rings in a concentration-dependent manner. In addition, ADIS attenuates transient contractions in Ca2+-free medium containing EGTA (1 mM) induced by PE (10 μM) and caffeine (20 mM). By contrast, relaxation was not affected by tetraethylammonium (TEA, 5 mM), 4-aminopyridine (4-AP, 1 mM), glibenclamide (10 μM), barium chloride (BaCl2, 1 mM), and 1H-[1,2,3]oxadiazolo[4,3-α]quinoxalin-1-one (ODQ, 1 μM). Significance: These findings reveal the vasorelaxant effect of ADIS, through endothelium-independent pathway. It acts as a Ca2 + channel blocker through both intracellular and extracellular Ca2 + release.
- Pantan, Rungusa,Onsa-Ard, Amnart,Tocharus, Jiraporn,Wonganan, Orawan,Suksamrarn, Apichart,Tocharus, Chainarong
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- Discovery of lysosome-targeted covalent anticancer agents based on isosteviol skeleton
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Covalent drugs play corresponding bioactivities by forming covalent bonds with the target, which possess many significant pharmacological advantages including high potency, ligand efficiency, and long-lasting effects. However, development of covalent inhibitors is a challenge due to their presumed indiscriminate reactivity. Here, we report the discovery of series of lysosome-targeting covalent anticancer agents by introducing nitrogenous bases to the modified isosteviol skeleton in order to minimize the toxicity and increase the selectivity. By introducing the electrophilic α, β-unsaturated ketones into the A- and D-rings of isosteviol, the cytotoxicity of the obtained compounds were greatly increased. Further nitrogen-containing modifications to the D-ring led to the discovery of novel molecules that targeted lysosomes, and of which, compound 30 was the most potent and selective antiproliferative one to kill A549 cells in vitro and in vivo. Mechanism investigation revealed that compound 30 was trapped into lysosomes and damaged lysosomes to cause cell death.
- Liu, Jun,Li, Lin,Li, Xiaobin,Wang, Xin,Zhao, Xiaoyu,Qiao, Yanan,Xu, Yuliang,Sun, Yong,Qian, Lilin,Liu, Zhaopeng,Ji, Aiguo,Lou, Hongxiang
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- The neuroprotective effects of isosteviol against focal cerebral ischemia injury induced by middle cerebral artery occlusion in rats
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Occlusion of a cerebral artery impairs blood flow leading to neuronal death. Reperfusion of the tissue is associated with inflammation, increased reactive oxygen species, necrosis and apoptosis. Hence, damage to the brain will continue even after the blood flow is restored. Isosteviol has been demonstrated to have protective effects against ischemia-reperfusion (IR) injury in the rat heart and the current study was undertaken to determine whether it is also effective in preventing IR injury in the brain. Rats were divided into six groups: a sham-operation control group and 5 IR groups that were pre-treated with either isosteviol 5 mg-kg-1,10 mg-kg-1,20 mg-kg -1, nimodipine 5 mg-kg-1, or saline. Cerebral ischemia was in-duced for 2 hours. Twenty-two hours after reperfusion the rats were assessed for neurobeha-vioral deficit, infarct volume, histological changes, and malondialdehyde, superoxide dismutase (SOD), Bcl-2 and NF-kB levels in brain tissue. Pre-treatment with isosteviol reduced infarct volume, ameliorated cell death and infiltration of neutrocytes, improved neuro-locomotor activity, increased SOD activity, induced Bcl-2, suppressed lipid superoxidation and the expression of NF-kB, and therefore retarded necrosis and apoptosis of neurons and inflammation. These positive effects were dose-dependent with an isosteviol dose of 20 mg-kg-1, thus being as effective as nimodipine.
- Xu, Deyi,Du, Wenfeng,Zhao, Lei,Davey, Andrew K.,Wang, Jiping
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- Microbial Transformation of Isosteviol and Inhibitory Effects on Epstein-Barr Virus Activation of the Transformation Products
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Microbial transformation of isosteviol (2), a beyerane-type diterpenoid obtained from stevioside (1) by acid hydrolysis, yielded 7β -hydroxyisosteviol (3), 11β-hydroxyisosteviol (5), and 12β -hydroxyisosteviol (6) by the fungus Aspergillus niger, 17-hydroxyisosteviol (7) by the fungus Glomerella cingulata, and 3 and 7-oxoisosteviol (4) by the fungus Mortierella elongate. The five metabolites, 3-7, along with 1 and 2 were evaluated for their inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells as a primary screening test for inhibitors of tumor promoters. All the diterpenes tested showed potent inhibitory effects, with the five metabolites 3-7 exhibiting more potent effects.
- Akihisa, Toshihiro,Hamasaki, Yusuke,Tokuda, Harukuni,Ukiya, Motohiko,Kimura, Yumiko,Nishino, Hoyoku
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- Potent vasorelaxant analogs from chemical modification and biotransformation of isosteviol
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Isosteviol (1) has been reported to exhibit moderate vasorelaxant activity. In order to enhance the bioactivity of this compound, chemical modification of 1 to the dihydro analog, ent-16β-hydroxybeyeran-19-oic acid (2), was undertaken. Compound 2 was then converted to the corresponding acetate derivative, ent-16β-acetoxybeyeran-19-oic acid (3). Biotransformation of compounds 1-3 by the fungus Cunninghamella echinulata NRRL 1386 was investigated and the metabolites 4-9 were obtained. The substrates and their metabolites were subjected to in vitro rat aorta relaxant activity evaluation. The metabolite 4, ent-7α-hydroxy-16-ketobeyeran-19-oic acid, exhibited the most highly potent activity, with EC50 of 3.46 nM, whereas the parent compound 1 showed relatively low activity (EC50 57.41 nM). A 17-fold increase in vasorelaxant activity of the analog 4 relative to compound 1 is of particular significant. Compound 4 exerted vasorelaxant activity at particularly low concentration and the vasorelaxant profile reached maximum at relatively low concentration, especially when compared with acetylcholine, the positive control.
- Wonganan, Orawan,Tocharus, Chainarong,Puedsing, Chonticha,Homvisasevongsa, Sureeporn,Sukcharoen, Oratai,Suksamrarn, Apichart
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- The synthesis and crystal structure of (4α,8β,13β,16β) -13-methyl-16,18-diol-17-norkaurane: A simultaneous reduction product of isosteviol
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(4α,8β,13β,16β)-13-methyl-16,18-diol-17-norkaurane was synthesized by esterification and reduction of isosteviol, respectively. The structure of the title compound was established by spectral analysis and X-ray diffraction studies. The compound crystallizes in the orthorhombic space group P212121 with unit cell parameters: a = 7.3705 (14) A, b = 13.508 (3) A, c = 20.139 (4) A, V = 2005.1 (7) A3, Z = 4. The conformation of rings A and B is chair, whereas the conformation of ring C is unsymmetrical distorted chair. The stereochemistry of the A/B and B/C ring junctions is trans, while the five-membered ring D adopts an envelope conformation. Springer Science+Business Media, LLC 2010.
- Chen, Junqing,Sun, Min,Cai, Jin,Cao, Meng,Zhou, Wen,Ji, Min
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- Microbial Transformations of Two Beyerane-Type Diterpenes by Cunninghamella echinulata
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Microbial transformations of two tetracyclic beyerane-type diterpenes, ent-16β-oxobeyeran-19-oic acid (1) and its chemical reduction product, ent-16β-hydroxybeyeran-19-oic acid (2), by the filamentous fungus Cunninghamella echinulata ATCC 8688a yielded eight metabolites (3-10). Incubation of the substrate 2 with C. echinulata afforded three new hydroxylated ones (3-5) along with two known ones (6-7), while incubation of 1 gave three known ones (8-10). The new compounds were characterized by 1D and 2D NMR as well as HRESIMS analysis, and the stereostructures of 3 and 4 were confirmed by X-ray crystallography. The bioreactions were involved not only in stereoselective incorporation of hydroxyl groups at inert positions C-7,-9,-12, and-14 of the two beyerane diterpenes but also in glucosidation at C-19 of 2. This is the first report on the biotransformation of the diterpenes by using C. echinulata. All compounds were assayed for their α-glucosidase inhibitory, neurotrophic, anti-inflammatory, and phytotoxic activity, and only in neurotrophic assay compounds, 2 and 9 were found to display nerve growth factor-mediated neurite-outgrowth promoting effects in PC12 cells; the others were inactive.
- Gao, Jin-Ming,Gao, Yu-Qi,Lee, Shoei-Sheng,Li, Ruoxin,Wang, Wei-Wei
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- Discovery of novel, potent, isosteviol-based antithrombotic agents
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Thrombosis is a pathological coagulation process and can lead to many serious thrombotic diseases. Here, we report a novel potent antithrombotic compound (6k) based on isosteviol with anticoagulant and antiplatelet activities. 6k selectively inhibited FXa (Ki = 0.015 μM) against a panel of serine proteases and showed excellent anticoagulant activity (significant prolongation of ex vivo PT and aPTT over the vehicle, p 0.01). 6k also significantly inhibited ADP-induced platelet aggregation in rats relative to the vehicle (p 0.01). Furthermore, 6k exhibited potent ex vivo and in vivo antithrombotic activity in rats relative to the vehicle (p 0.01 and p 0.0001, respectively). Novel structure 6k, with potent antithrombotic activity, is expected to lead a promising approach for the development of antithrombotic agents.
- Chen, Peng,Zhang, Dianwen,Li, Meng,Wu, Qiong,Lam, Yuko P.Y.,Guo, Yan,Chen, Chen,Bai, Nan,Malhotra, Shipra,Li, Wei,O'Connor, Peter B.,Fu, Hongzheng
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- 16-Aza-ent-beyerane and 16-aza-ent-trachylobane: Potent mechanism-based inhibitors of recombinant ent-kaurene synthase from Arabidopsis thaliana
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The secondary ent-beyeran-16-yl carbocation (7) is a key branch point intermediate in mechanistic schemes to rationalize the cyclic structures of many tetra- and pentacyclic diterpenes, including ent-beyerene, ent-kaurene, ent-trachylobane, and ent-atiserene, presumed precursors to >1000 known diterpenes. To evaluate these mechanistic hypotheses, we synthesized the heterocyclic analogues 16-aza-ent-beyerane (12) and 16-aza-ent-trachylobane (13) by means of Hg(II)- and Pb(IV)-induced cyclizations onto the Δ12 double bonds of tricyclic intermediates bearing carbamoylmethyl and aminomethyl groups at C-8. The 13,16-seco-16-norcarbamate (20a) was obtained from ent-beyeran-16-one oxime (17) by Beckmann fragmentation, hydrolysis, and Curtius rearrangement. The aza analogues inhibited recombinant ent-kaurene synthase from Arabidopsis thaliana (GST-rAtKS) with inhibition constants (IC50 = 1 × 10-7 and 1 × 10 -6 M) similar in magnitude to the pseudo-binding constant of the bicyclic ent-copalyl diphosphate substrate (Km = 3 × 10 -7 M). Large enhancements of binding affinities (IC50 = 4 × 10-9 and 2 × 10-8 M) were observed in the presence of 1 mM pyrophosphate, which is consistent with a tightly bound ent-beyeranyl+/pyrophosphate- ion pair intermediate in the cyclization-rearrangement catalyzed by this diterpene synthase. The weak inhibition (IC50 = 1 × 10-5 M) exhibited by ent-beyeran-16-exo-yl diphosphate (11) and its failure to undergo bridge rearrangement to kaurene appear to rule out the covalent diphosphate as a free intermediate. 16-Aza-ent-beyerane is proposed as an effective mimic for the ent-beyeran-16-yl carbocation with potential applications as an active site probe for the various ent-diterpene cyclases and as a novel, selective inhibitor of gibberellin biosynthesis in plants.
- Roy, Arnab,Roberts, Frank G.,Wilderman, P. Ross,Zhou, Ke,Peters, Reuben J.,Coates, Robert M.
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- Validation of an HPLC method for direct measurement of steviol equivalents in foods
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Steviol glycosides are intense natural sweeteners used in foods and beverages. Their acceptable daily intake, expressed as steviol equivalents, is set at 0-4 mg/kg body weight. We report the development and validation of a RP-HPLC method with fluorometric detection of derivatized isosteviol, formed by acid hydrolysis of steviol glycosides. Dihydroisosteviol was used as an internal standard. Using this method, the amount of steviol equivalents in commercial steviol glycoside mixtures and different foods can be directly quantified. The method was successfully tested on strawberry jam, low-fat milk, soft drink, yogurt and a commercial mixture of steviol glycosides. Calibration curves were linear between 0.01 and 1.61 mM steviol equivalents, with a quantification limit of 0.2 nmol. The % RSD of intra-day precision varied between 0.4% and 4%, whereas inter-day precision varied between 0.4% and 5%, for high and medium concentrations, and between 3% and 8% for low concentrations. Accuracy of the analysis varied between 99% and 115%.
- Bartholomees, Uria,Struyf, Tom,Lauwers, Olivier,Ceunen, Stijn,Geuns, Jan M.C.
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- Microbial transformations of isosteviol
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Microbial transformations of the tetracyclic diterpenoid isosteviol (ent-16-ketobeyeran-19-oic acid) (2) have revealed that isosteviol is metabolized by Cunninghamella bainieri, Actinoplanes sp., Mucor recurvatus, and Cunninghamella blakesleeana to yield five new metabolites, ent-11α,12α-dihydroxy-16-ketobeyeran-19-oic acid (5), ent-11α,12α,17-trihydroxy-16-ketobeyeran-19-oic acid (6), ent-12α, 15α-dihydroxy-16-ketobeyeran-19-oic acid (7), ent-7α,15α-dihydroxy-16-ketobeyeran-19-oic acid (8), and ent-9α-hydroxy-16-ketobeyeran-19-oic acid (9), together with three known metabolites, ent-7α-hydroxy-16-ketobeyeran-19-oic acid (3), ent-7β-hydroxy-16-ketobeyeran-19-oic acid (4), and ent-12α-hydroxy-16-ketobeyeran-19-oic acid (10). The structures of these metabolites were established on the basis of HRFABMS and 1D and 2D NMR spectral data. In addition, metabolites 3-10 were tested for antihypertensive activity and were found to be less active than the parent compound 2.
- Hsu, Feng-Lin,Hou, Chia-Chung,Yang, Li-Ming,Cheng, Juei-Tang,Chi, Tzong-Cherng,Liu, Pang-Chun,Lin, Shwu-Jiuan
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- Synthesis, cytotoxic activity evaluation and HQSAR study of novel isosteviol derivatives as potential anticancer agents
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A series of novel isosteviol derivatives bearing amino alcohol and thiourea fragments have been stereo-selectively synthesized and screened for their in vitro cytotoxic activities against three human cancer cell lines (HCT-116, HGC-27 and JEKO-1). The results demonstrated that these compounds exhibited prominent cytotoxicities. Especially, the compound Iw displayed the most potent anticancer activities against HCT-116 cell with IC50 value of 1.450 μM. On the basis of this bioassay results, these derivatives were further investigated by the hologram quantitative structure-activity relationship (HQSAR) technique. The optimal HQSAR model with q2 Combining double low line 0.663, r2 Combining double low line 0.895, SEE Combining double low line 0.179 was generated using A/B/H/Ch as fragment distinction parameters and 4-7 as fragment size. This model was employed to predict the cytotoxic activities of test set compounds, and the predicted values were in good agreement with the experimental results. The contribution maps derived from the optimal model explained the individual atomic contribution to the total activity of single molecule.
- Liu, Cong-Jun,Yu, Shu-Ling,Liu, Yan-Ping,Dai, Xing-Jie,Wu, Ya,Li, Rui-Jun,Tao, Jing-Chao
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- Diterpene glycosides from stevia rebaudiana
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Three novel diterpene glycosides were isolated for the first time from the commercial extract of the leaves of Stevia rebaudiana, along with several known steviol glycosides, namely stevioside, rebaudiosides A-F, rubusoside and dulcoside A. The new compounds were identified as 13-[(2-O-β-D- glucopyranosyl-3-O-β-D-glucopyranosyl-β-Dglucopyranosyl) oxy] ent-kaur-15-en-19-oic acid (1), 13-[(2-O-β-D-glucopyranosyl-3-O-β- D-glucopyranosyl-β-D-glucopyranosyl)oxy]-16β-hydroxy-ent-kauran-19- oic acid (2) and 13-methyl-16-oxo-17-nor-ent-kauran-19-oic acid-β-D- glucopyranosyl ester (3) on the basis of extensive 2D NMR and MS spectroscopic data as well as chemical studies.
- Chaturvedula, Venkata Sai Prakash,Upreti, Mani,Prakash, Indra
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- Synthesis, cytotoxic activity, and 2D- and 3D-QSAR studies of 19-carboxyl-modified novel isosteviol derivatives as potential anticancer agents
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Two series of novel acylthiosemicarbazide and oxadiazole fused-isosteviol derivatives were synthesized based on the 19-carboxyl modification. The target compounds were evaluated for their cytotoxicities against three cancer cell lines (HCT-116, HGC-27, an
- Liu, Cong-Jun,Zhang, Tao,Yu, Shu-Ling,Dai, Xing-Jie,Wu, Ya,Tao, Jing-Chao
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- Biotransformation of isosteviol by Fusarium verticilloides
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The biotransformation of isosteviol (ent-16-ketobeyeran-19-oic acid) by Fusarium verticilloides (Sacc.) Nirenberg 133 produced ent-7β-hydroxy-16- ketobeyeran-19-oic acid and ent-12α-hydroxy-16-ketobeyeran-19-oic acid. The metabolites were isolated and characterized by spectroscopic methods.
- De Oliveira, Bras H.,Strapasson, Rogerio A.
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- Synthesis and in vivo screening of isosteviol derivatives as new cardioprotective agents
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Isosteviol, an ent-beyerane diterpenoid, has been repeatedly reported to possess potent cardioprotective activity. With the aim of discovering new cardioprotective derivatives from isosteviol, 47 compounds, including 40 new ones, were synthesized and eval
- Zhang, Hanyuan,Liu, Bo,Xu, Geng,Xu, Chao,Ou,Liu, Jiansong,Sun, XiaoOu,Zhao, Yu
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- INHIBITORS OF ANTIBIOTIC RESISTANCE MEDIATED BY ARN T
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The present invention relates to diterpene compounds of general formula (I) capable of contrasting the antibiotic-resistance mediated by the ArnT enzyme, to their use as a medicament, in particular for use as an adjuvant of an antibiotic therapy in the treatment of antibiotic-resistant bacterial infections. The invention relates also to associations of one or more of the compounds of formula (I) with at least another active ingredient, in particular an antibacterial agent and/or an antibiotic, and compositions comprising one or more compounds of formula (I) or the association according to the present invention and at least one pharmaceutically acceptable excipient and/or carrier as well as to products, in particular medical devices, comprising at least a compound, an association or a composition according to the present invention. Moreover, the invention relates to the use of compounds of formula (I) to sensitize a bacterium to an antibacterial agent or an antibiotic, for example, colistin (polymyxin E) or polymyxin B and to an in vivo or in vitro method for sensitizing a bacterium to an antibacterial agent or an antibiotic comprising the exposure of said bacterium to one or more compounds of formula (I) together with colistin.
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Page/Page column 23-24
(2021/01/29)
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- Isosteviol amphiphilic derivative and preparation method thereof
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The invention discloses structures of isosteviol amphiphilic derivatives and a preparation method of the isosteviol amphiphilic derivatives, and belongs to the technical field of supramolecular chemistry. The compound is based on a natural product isosteviol, the nineteenth position of the compound is connected with a polyether chain, and the ends of the compound are different quaternary ammonium salts; the structural formula of the compound is shown in figure 1, wherein R is pyridine quaternary ammonium salt, imidazole quaternary ammonium salt and the like.
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Paragraph 0027-0028
(2021/04/10)
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- Ent-Beyerane Diterpenes as a Key Platform for the Development of ArnT-Mediated Colistin Resistance Inhibitors
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Colistin is a last-resort antibiotic for the treatment of multidrug resistant Gram-negative bacterial infections. Recently, a natural ent-beyerene diterpene was identified as a promising inhibitor of the enzyme responsible for colistin resistance mediated by lipid A aminoarabinosylation in Gram-negative bacteria, namely, ArnT (undecaprenyl phosphate-alpha-4-amino-4-deoxy-l-arabinose arabinosyl transferase). Here, semisynthetic analogues of hit were designed, synthetized, and tested against colistin-resistant Pseudomonas aeruginosa strains including clinical isolates to exploit the versatility of the diterpene scaffold. Microbiological assays coupled with molecular modeling indicated that for a more efficient colistin adjuvant activity, likely resulting from inhibition of the ArnT activity by the selected compounds and therefore from their interaction with the catalytic site of ArnT, an ent-beyerane scaffold is required along with an oxalate-like group at C-18/C-19 or a sugar residue at C-19 to resemble L-Ara4N. The ent-beyerane skeleton is identified for the first time as a privileged scaffold for further cost-effective development of valuable colistin resistance inhibitors.
- Ascenzioni, Fiorentina,Botta, Bruno,Calcaterra, Andrea,Cammarone, Silvia,Cappiello, Floriana,Casciaro, Bruno,Cavinato, Luca,Corradi, Silvia,Erazo, Silvia,Ghirga, Francesca,Imperi, Francesco,Loffredo, Maria Rosa,Lucantoni, Federica,Mangoni, Maria Luisa,Mori, Mattia,Quaglio, Deborah,Stefanelli, Roberta,Vergine, Valeria
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p. 10891 - 10901
(2020/09/23)
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- Antileishmanial activity and cytotoxicity of ent-beyerene diterpenoids
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We describe the in vitro activity of two natural isomeric ent-beyerene diterpenes, several derivatives and synthetic intermediates. Beyerenols 1 and 2 showed EC50 of 4.6 ± 9.4 and 5.3 ± 9.4 μg/mL against amastigotes of L. (V) brazilensis, with
- Murillo, Jilmar A.,Gil, Juan F.,Upegui, Yulieth A.,Restrepo, Adriana M.,Robledo, Sara M.,Qui?ones, Winston,Echeverri, Fernando,San Martin, Aurelio,Olivo, Horacio F.,Escobar, Gustavo
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p. 153 - 160
(2018/11/27)
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- Endocyclic double bond isomers and by-products from rebaudioside A and stevioside formed under acid conditions
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The hydrolysis reaction of rebaudioside A and stevioside was studied under mild and strong acidic conditions at different temperatures and times. Exposure of rebaudioside A to vigorous acid conditions yielded three different aglycone cores which were puri
- Perera, Wilmer H.,Docampo, Maite L.,Wiggers, Frank T.,Hufford, Charles D.,Fronczek, Frank R.,Avula, Bharathi,Khan, Ikhlas A.,McChesney, James D.
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p. 163 - 170
(2018/04/20)
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- Polyether urea bridged chiral molecular tweezers and preparation and application thereof
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The invention discloses polyether urea bridged chiral molecular tweezers and preparation and application thereof. The polyether urea bridged chiral molecular tweezers are structurally shown as formula(I) or formula (II) shown in the description. The invention also provides application of the polyether urea bridged chiral molecular tweezers in the recognition of a chiral molecular guest; the chiral molecular guest is D/L-amino acid ester hydrochloride. The polyether urea bridged chiral molecular tweezers synthesized herein have certain property of chirally recognizing D/L-amino acid ester hydrochloride and are applicable to chiral recognition and separation of enantiomers.
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Paragraph 0042; 0043
(2018/11/22)
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- Isosteviol derivative and its preparation and use (by machine translation)
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The invention discloses isosteviol derivative and its preparation and application, isosteviol derivatives of formula I compound of formula, the formula II compound of formula; Wherein Representative is a single or double bond; R1 And R2 Independently selected from the group consisting of: hydrogen atom, methylene and substituent is C1 - C10 Of amine, can replace the carbonyl or methylene precursor structure, such as Mannich base, imine salt; Wherein R3 Selected from OR4 OCOCHCHR5 , OR4 R6 , NR4 , OR4 X⊕ (Y)3 Z⊙ ; R4 The selected hydrocarbon, ether, the inner wall of the; R5 Is selected from trifluoromethyl, phenyl, benzyl, pyridyl, furyl, pyrrolyl, indolyl, aminoethyl; R6 Selected from H atom, southernwood [...], benzyl, type II of the nucleus in order to form the dimer; X is selected from the P atom or N atom; is selected from methyl, ethyl, isopropyl, butyl, phenyl; Z is selected from F, Cl, Br, I. (by machine translation)
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Paragraph 0063-0065
(2018/09/14)
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- Stevioside derivative as well as preparation method and application thereof
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The invention discloses a stevioside derivative as well as a preparation method and application thereof. The stevioside derivative is a compound or pharmaceutically acceptable salt shown in a formulaI which is shown in the specification, wherein a. a sign shown in the specification represents a single bond or double bonds; b. R1, R4 and R5 are respectively independently selected from a hydrogen atom, methylene, an oxygen atom and amino alkyl having a substituent group of C1 to C10; R1 and R5 are precursor structures capable of replacing carbonyl or methylene, such as Mannich alkali and iminesalt; c. R2 and R3 are respectively independently selected from methylene, an oxygen atom, NOH, NR7, NOR8 and the like; d. R6 is selected from methyl, hydroxyl, OR9 and OCOR10; (OCO represents an ester group); e. R7, R8, R9 and R10 are respectively independently selected from hydrocarbyl of C1 to C10 (such as alkyl, a naphthenic base, alkenyl and alkynyl), aryl (such as phenyl, naphthyl replaced at any position, and all pentabasic, hexahydric and macrocyclic aromatic heterocyclic groups or various substitutional aryl), hydroxyl, carboxyl, an ester group, benzyl, metal (such as K, Na and Li) oran ion (such as NH).
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Paragraph 0053-0056
(2019/07/29)
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- Elevation of the plasma HDL-cholesterol level
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The present invention relates to the use of isosteviol, steviol, and related compounds for elevating the plasma HDL-cholesterol level. The invention furthermore relates to the use of these compounds for reducing the body weight of a subject and/or lowering the plasma triglyceride level of a subject, including a concomitant elevation of the plasma HDL-cholesterol level. Preferably the compounds used are isosteviol and/or steviol, or pharmaceutically acceptable salts, solvates or prodrugs thereof. The compounds may furthermore be administered in combination with one or more further active compounds, such as e.g. LDL-cholesterol lowering agents. The invention furthermore relates to a method for elevating the plasma HDL-cholesterol level in a subject by administering to a subject in need of such treatment a plasma HDL-cholesterol level elevating amount of the compounds, described herein.
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Page/Page column 26; 27
(2016/05/11)
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- Chiral crown ether containing ent-beyeren skeleton, and preparation method and application thereof
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The invention provides a chiral crown ether containing ent-beyeren skeleton disclosed as Formula (I) or Formula (II) and a preparation method thereof. The chiral crown ether has certain application prospects as a receptor in the aspect of chiral molecular guest identification, wherein the chiral molecular guest comprises chiral ammonia compounds and chiral hydroxyl compounds, for example D/L-phenylglycine methyl ester hydrochloride or D/L-phenylglycine ethyl ester hydrochloride. The chiral crown ether compound using the ent-beyeren structure as the chiral source has the advantages of accessible raw materials, adjustable structure, simple preparation process and the like, can be used as a receptor in a chiral molecular identification system, and is hopeful to be applied to the field of chiral identification separation.
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Paragraph 0027-0028
(2017/02/09)
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- Synthesis of skeletally diverse and stereochemically complex library templates derived from isosteviol and steviol
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We have applied a diversity-oriented approach for the synthesis of skeletally diverse and stereochemically complex templates for small-molecule library production by performing Beckmann rearrangement and Beckmann fragmentation reactions on the bicyclo[3.2.1]octane rings of steviol and isosteviol, aglycones derived from the diterpene natural product stevioside. The optimization of these two reaction pathways is presented along with the successful application of a photo-Beckmann rearrangement. This work also led to the discovery of cyano-Prins-type and Thorpe-Ziegler-type cyclization reactions.
- Hutt, Oliver E.,Doan, Trinh L.,Georg, Gunda I.
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supporting information
p. 1602 - 1605
(2013/07/05)
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- Cytotoxic and apoptosis-inducing activities of steviol and isosteviol derivatives against human cancer cell lines
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Seventeen steviol derivatives, i.e., 2-18, and 19 isosteviol derivatives, i.e., 19-37, were prepared from a diterpenoid glycoside, stevioside (1). Upon evaluation of the cytotoxic activities of these compounds against leukemia (HL60), lung (A549), stomach (AZ521), and breast (SK-BR-3) cancer cell lines, nine steviol derivatives, i.e., 5-9 and 11-14, and five isosteviol derivatives, i.e., 28-32, exhibited activities with single-digit micromolar IC50 values against one or more cell lines. All of these active compounds possess C(19)-O-acyl group, and among which, ent-kaur-16-ene-13,19-diol 19-O-4′,4′,4′-trifluorocrotonate (14) exhibited potent cytotoxicities against four cell lines with IC50 values in the range of 1.2-4.1 μM. Compound 14 induced typical apoptotic cell death in HL60 cells upon evaluation of the apoptosis-inducing activity by flow-cytometric analysis. These results suggested that acylation of the 19-OH group of kaurane- and beyerane-type diterpenoids might be useful for enhancement of their cytotoxicities with apoptosis-inducing activity. Copyright
- Ukiya, Motohiko,Sawada, Shingo,Kikuchi, Takashi,Kushi, Yasunori,Fukatsu, Makoto,Akihisa, Toshihiro
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p. 177 - 188
(2013/04/23)
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- Design and stereoselective synthesis of novel isosteviol-fused pyrazolines and pyrazoles as potential anticancer agents
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Two series of novel isosteviol-fused pyrazoline and pyrazole derivatives were facilely synthesized via intramolecular 1,3-dipolar cycloaddition and condensation reaction, respectively. All compounds were characterized by NMR, IR and HRMS spectra. The stereochemistry of compounds 9b, 10, 11a and 11v were further confirmed by X-ray crystallographic analysis. The antiproliferative activities of the structurally related pyrazoline and pyrazole derivatives were tested in vitro on four human malignant cell lines (SGC 7901, A549, Raji and HeLa): Our results revealed that isosteviol-fused pyrazole derivatives exhibited noteworthy cytotoxic activities. Among them, 2,4-di-Cl-phenylpyrazole derivative 11t displayed better cytotoxities with IC50 values: 2.71, 3.18, 1.09 and 13.52 mM against SGC 7901, A549, Raji and HeLa, respectively, compared to cisplatin (IC50 values: 7.56, 17.78, 17.32 and 14.31 μM, respectively).
- Zhu, Song-Lin,Wu, Ya,Liu, Cong-Jun,Wei, Chang-Yong,Tao, Jing-Chao,Liu, Hong-Min
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- Fungal transformation of isosteviol lactone and its biological evaluation for inhibiting the AP-1 transcription factor
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A number of hydroxylated diterpenoids were obtained from the microbial transformation of isosteviol lactone (4α-carboxy-13α-hydroxy-13,16-seco-ent-19-norbeyeran-16-oic acid 13,16-lactone) (2) with Mucor recurvatus MR 36, Aspergillus niger BCRC 31130, and
- Chou, Bo-Hon,Yang, Li-Ming,Chang, Shwu-Fen,Hsu, Feng-Lin,Lo, Chia-Hsin,Lin, Wen-Kuang,Wang, Li-Hsuan,Liu, Pan-Chun,Lin, Shwu-Jiuan
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experimental part
p. 759 - 764
(2010/06/16)
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- Synthesis and crystal structure of benzoyloxymethyl (4α,8β, 13β)-13-methyl-16-oxo-17-norkauran-18-carbonate Ester
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Isosteviol derivative: benzoyloxymethyl (4α,8β,13β)-13- methyl-16-oxo-17-norkauran-18-carbonate ester was synthesized by esterification of isosteviol with chloromethyl benzoate and its crystal structure was determined by X-ray diffraction method. The compound crystallizes in the triclinic space group P1 with unit cell parameters: a = 8.784(3) A, b = 9.079(3) A, c = 15.950(6) A, α = 79.343(6)°, β = 79.061(5)°, γ = 89.849(5)°, Z= 2. The conformation of rings A and B is chair, whereas the conformation of ring C is unsymmetrical twist chair. The carbonyl group at the C20 is coplanar with the benzene ring. The fragment of the ester group occupying the pseudoaxial site of C1 position adopts a zigzag conformation.
- Cai, Jin,Zhou, Wen,Chen, Junqing,Sun, Min,Ji, Min
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experimental part
p. 108 - 111
(2009/10/10)
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- Stereoselective synthesis of bioactive isosteviol derivatives as α-glucosidase inhibitors
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Considerable interest has been attracted in isosteviol and its derivatives because of their large variety of pharmacological activities. In this project, a series of novel compounds containing hydroxyl, hydroxymethyl group and heteroatom-containing frameworks fused with isosteviol structure were synthesized and evaluated as α-glucosidase inhibitors, aimed at clarifying the structure-activity correlation. The results indicated that these isosteviol derivatives were capable of inhibiting in vitro α-glucosidase with moderate to good activities. Among them, indole derivative 15b exhibited the highest activities and thus may be exploitable as a lead compound for the development of potent α-glucosidase inhibitors.
- Wu, Ya,Yang, Jing-Hua,Dai, Gui-Fu,Liu, Cong-Jun,Tian, Guo-Qiang,Ma, Wen-Yan,Tao, Jing-Chao
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experimental part
p. 1464 - 1473
(2009/09/05)
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- THE USE OF KAURENE COMPOUNDS IN THE MANUFACTURE OF MEDICAMENTS FOR THE TREATMENT OF ISCHEMIC DISEASES
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The invention relates the pharmaceutical use of kaurene compounds of formula (1) in treating and preventing coronary disease, stroke, cerebral ischemia and arrhythmia etc. The said compounds also have significant protecting effects against cerebral ischemic infarction. Wherein R 1 : hydrogen, hydroxyl or alkoxy R 2 : carboxyl, carboxylate, acyl halides, aldehyde, methylhydroxyl, and ester, acylamide, acyl or ether group hydrolysable to carboxyl. R 3 ,R 4 ,R 5 ,R 6 ,R 8 : independently, oxygen, hydroxyl, methylhydroxyl, and ester or alkyloxymethyl group hydrolysable to methylhydroxyl, R 7 : methyl, hydroxyl, and ester or alkyloxymethyl hydrolysable to methylhydroxyl,. R 9 : methylene or oxygen.
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Page/Page column 10
(2008/06/13)
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- Transformation of isosteviol oxime to a lactone under Beckmann reaction conditions
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Heating the 16-E-oxime of isosteviol (ent-16-E-hydroxyiminobeyeran-19-oic acid) with concentrated hydrochloric acid (or 25% H2SO4) at 110°C leads to the formation of lactone of 4α-carboxy-13α- hydroxy-13,16-seco-ent-19-norbeyeran-16-oic acid as the main product, whereas approximately equal quantities of this lactone and lactam of 4α-carboxy-13α-amino-13,16-seco-ent-19-norbeyeran-16-oic acid are formed by heating the 16-E-oxime of isosteviol with concentrated hydrochloric acid in an ampoule at 180°C.
- Militsina, Olesya I.,Kovyljaeva, Galina I.,Bakaleynik, Galina A.,Strobykina, Irina Yu.,Kataev, Vladimir E.,Alfonsov, Vladimir A.,Musin, Rashid Z.,Beskrovny, Dmitry V.,Litvinov, Igor A.
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- Design and synthesis of an α-mannosyl terpenoid as selective inhibitor of P-selectin
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In an effort to develop the structural and functional mimics of the tetrasaccharide sialyl Lewis x as selective inhibitors of P-selectin, we have designed a mannosyl terpenoid derivative that selectively inhibits P-selectin within an IC50 value of 60 μM, but exhibits no inhibition activity against E- and L-selectins.
- Ikeda, Tsuyoshi,Kajimoto, Tetsuya,Kondo, Hirosato,Wong, Chi-Huey
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p. 2485 - 2490
(2007/10/03)
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