- Synthesis, biological evaluation and molecular modeling of novel triazole-containing berberine derivatives as acetylcholinesterase and β-amyloid aggregation inhibitors
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A series of novel triazole-containing berberine derivatives were synthesized via the azide-alkyne cycloaddition reaction. Their biological activity as inhibitors of both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) were evaluated. Among t
- Shi, Anding,Huang, Ling,Lu, Chuanjun,He, Feng,Li, Xingshu
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- Mitochondria-targeting nanomedicine self-assembled from GSH-responsive paclitaxel-ss-berberine conjugate for synergetic cancer treatment with enhanced cytotoxicity
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Mitochondria play a fundamental role in plenty of cellular metabolic processes, and mitochondria-homing drug delivery is a promising and effective strategy for cancer treatment. Paclitaxel (PTX) is a broad-spectrum anticancer drug, but its therapeutic eff
- Cheng, Yu,Ji, Yuanhui
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- A novel berberine-based colorimetric and fluorimetric probe for hydrazine detection
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Hydrazine in water and soil has caused serious diseases that threaten human health. It is critical to develop a simple and effective method for hydrazine detection. In this work, a simple fluorescent probe (BP) for hydrazine detection was synthesized from the isoquinoline alkaloid berberine. The probe has a short synthesis route (2 steps), low detection limit (1.37 μM), excellent fluorescence properties, and convenient naked-eye detection. In addition, BP displayed excellent selectivity and specificity over other metal ions, anions, and amines. Moreover, BP was also successfully used to detect hydrazine gas at different concentrations. This journal is
- Ruan, Shutang,Gao, Yu,Wang, Yunyun,Li, Mingxin,Yang, Haiyan,Song, Jie,Wang, Zhonglong,Wang, Shifa
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- Conversion of berberine into berberrubine by selective demethylation under microwave irradiation
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Berberine, a natural alkaloid, underwent selective demethylation under microwave irradiation to form an important bioactive compound, berberrubine in excellent yield.
- Das, Biswanath,Srinivas
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- Triple stimuli-responsive supramolecular nanoassembly with mitochondrial targetability for chemophotothermal therapy
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Mitochondria play crucial roles in a variety of cellular physiological processes, mitochondria-accumulating drug delivery has drawn pronounced attention in the field of cancer theranostics. Camptothecin (CPT) is a DNA Topoisomerase I inhibitor and exerts a broad-spectrum anticancer profile. Berberine (BBR) is able to perferably enter into cancer cell mitochondria and trigger the cell apoptosis. In this work, CPT and BBR were combined together (CPT-ss-BBR) through GSH-responsible disulfide bond, and then co-assembled with photosensitizer indocyanine green (ICG) into nanodrugs (CPT-ss-BBR/ICG NPs), which was driven through hydrophobic, π-π stacking and especially, electrostatic interactions of anions and cations as found by molecular dynamics simulations and quantum chemistry calculations. Our developed nanodrugs displayed an average size of ~168 nm and showed exceptional instability by irradiation presence, acid condition and high concentration of GSH, thereby eliciting the rapid disassembly and accelerating drug release. The better therapy effect of CPT-ss-BBR/ICG NPs on A549 cells might be attributed to triply stimuli-responsive rapid disassembly, preferable accumulation into mitochondria and combined chemotherapy and photothermal therapy, all of which directly rendered the notable loss of mitochondria membrane potential, high level of reactive oxygen species in cancer cells, accelerated the apoptosis of cancer cells and repressed the growth of tumors.
- Cheng, Yu,Ji, Yuanhui,Tong, Jiwei
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- Design, synthesis and biological evaluation of novel nitric oxide-donating protoberberine derivatives as antitumor agents
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A novel class of NO-donating protoberberine derivatives were synthesized and initially evaluated for their anti-hepatocellular carcinoma activities. Most of the compounds exhibited more potent activity against HepG2 cells than parent compounds berberine and palmatine. In particular, compound 15a exerted the strongest activity with an IC50 value of 1.36?μM. Moreover, most compounds released moderate levels of NO in?vitro, and the antitumor activity of 15a in HepG2 cells was remarkably diminished by an NO scavenger. Interestingly, compound 15a displayed a broad-spectrum antitumor efficacy and possessed good selectivity between tumor cells (HepG2, SMMC-7721, HCT-116, HL-60) and normal liver LO-2?cells. The mechanism studies revealed that 15a blocked the G2 phase of the cell cycle and induced apoptosis of HepG2 cells by mitochondrial depolarization. Furthermore, 15a inhibited tumor growth in H22 liver cancer xenograft mouse model by 62.5% (w/w), which was significantly superior to parent compound palmatine (41.6%, w/w). Overall, the current study may provide a new approach for the discovery of novel antitumor agents.
- Chen, Jichao,Wang, Tianyu,Xu, Shengtao,Lin, Aijun,Yao, Hequan,Xie, Weijia,Zhu, Zheying,Xu, Jinyi
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- Synthesis of 9-O-glycosyl-berberine derivatives and bioavailability evaluation
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To increase the bioavailability of berberine, three new 9-O-glycosyl-berberine derivatives, 9-O-glucosyl-(4a), 9-O-arabinosyl-(4b), and 9-O-erythrol-(4c) were obtained and confirmed by UV, 1HNMR, 13CNMR, and MS. The pharmacokinetic profiles of these synthetic compounds have been evaluated compared with berberine (1) and 9-O-alkyl-berberine (5) derivatives, which showed that maximum concentration (Cmax) and area under concentration-time curve (AUC) of 9-O-glycosyl-berberine increased dramatically. The results indicated that hydrophilic modification could significantly improve the bioavailability of berberine; 9-O-glycosyl-berberine might be a promising prodrug. Springer Science+Business Media, LLC 2011.
- Chen, Zhu,Ye, Xiaoli,Yi, Jun,Chen, Xin,Li, Xuegang
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- 11-Hydroxylation of Protoberberine by the Novel Berberine-Utilizing Aerobic Bacterium Sphingobium sp. Strain BD3100
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Protoberberine alkaloids, including berberine, palmatine, and berberrubine, are produced by medicinal plants and are known to have various pharmacological effects. We isolated two berberine-utilizing bacteria, Sphingobium sp. strain BD3100 and Rhodococcus sp. strain BD7100, from soil collected at a natural medicine factory. BD3100 had the unique ability to utilize berberine or palmatine as the sole carbon and energy source. BD3100 produced demethyleneberberine in berberine-supplemented medium. In a resting-cell incubation with berberine, BD3100 produced 11-hydroxyberberine; the structure of 11-hydroxyberberine was determined by detailed analysis of NMR and MS spectroscopic data. α-Naphthoflavone, miconazole, and ketoconazole, which are known inhibitors of cytochrome P450, interfered with BD3100 metabolism of berberine in resting cells. Inhibition by miconazole led to the production of a new compound, 11-hydroxydemethyleneberberine. In a resting-cell incubation with palmatine, BD3100 generated 11-hydroxypalmatine. This work represents the first report of the isolation and characterization of novel berberine-utilizing aerobic bacteria for the production of 11-hydroxylation derivatives of berberine and palmatine.
- Takeda, Hisashi,Ishikawa, Kazuki,Wakana, Daigo,Fukuda, Masao,Sato, Fumihiko,Hosoe, Tomoo
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- Hypolipidemic Berberine Derivatives with a Reduced Aromatic Ring C
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A series of aromatic and reduced berberine derivatives were synthesized. Their hypocholesterolemic activity was studied in vitro and in vivo. As a rule, berberine derivatives containing a reduced ring C were more capable of increasing the LDL receptor gene expression than the corresponding aromatic derivatives. Tests using a Triton WR1339-induced hypercholesterolemia model showed that 9-O-tosyltetrahydroberberine and 12-bromotetrahydroberberine possessed pronounced hypocholesterolemic activity and reduced the total cholesterol level by 33 and 27%; the triglyceride level, by 25 and 26%, respectively.
- Nechepurenko,Boyarskikh,Khvostov,Baev,Komarova,Filipenko,Tolstikova,Salakhutdinov
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- Novel Inhibitors of an Insect Pest Chitinase: Design and Optimization of 9-O-Aromatic and Heterocyclic Esters of Berberine
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OfChi-h, a lepidopteran-exclusive glycoside hydrolase family 18 (GH18) chitinase from the agricultural insect pest Ostrinia furnacalis, is a promising molecular target candidate for pest control and management. Berberine (BER), a traditional Chinese medic
- Chen, Lei,Cheng, Jiagao,Qian, Xuhong,Shao, Xusheng,Yang, Qing,Zhu, Ling
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- Preliminary studies of berberine and its semi-synthetic derivatives as a promising class of multi-target anti-parkinson agents
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Parkinson’s disease (PD) is a neurodegenerative disorder bearing motor and nonmotor symptoms. The treatment today is symptomatical rather than preventive or curative and this leaves the field open for the search of both novel molecular targets and drug candidates. Interference with α-synuclein fibrillation, monoamine oxidase (MAO) inhibition, modulation of adenosine receptors and the inhibition of specific phosphodiesterase (PDE) isoforms are some of the currently pursued strategies. We synthesised and studied some semi-synthetic berberine derivatives using a set of in silico tools. We evaluated their drug-likeness and tested the compounds against a set of target proteins involved in the onset or progression of PD, with a particular attention to MAO-B. Preliminary in vitro assay on MAO-B confirmed our in silico predictions.
- Ribaudo, Giovanni,Zanforlin, Enrico,Canton, Marcella,Bova, Sergio,Zagotto, Giuseppe
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- Antimicrobial activity of 9-O-acyl- and 9-O-benzoyl-substituted berberrubines
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In the course of a structure-activity relationship study on berberrubine derivatives, a series of compounds bearing 9-O-acyl- (4-6) and 9-O-benzoyl- (7) substituents was synthesized with the expectation of increasing the antimicrobial activity. One of the
- Hong, Sa Weon,Kim, Sung Han,Jeun, Jung Ae,Lee, Sang Jun,Kim, Sung Uk,Kim, Jung Han
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- Berberine derivatives with a long alkyl chain branched by hydroxyl group and methoxycarbonyl group at 9-position show improved anti-proliferation activity and membrane permeability in A549 cells
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Berberine (BBR) exhibits diverse bioactivities, including anticancer activity; but its poor druggability limits its applications. In this study, we designed and synthesized a series of 9-O position modified BBR derivatives aiming to improve its cell permeability and anticancer activity, utilizing a long alkyl chain branched by hydroxyl group and methoxycarbonyl group. Among these compounds, B10 showed 3.6-fold higher intracellular concentration than BBR, as well as 60-fold increased anti-proliferation activity against human lung cancer A549 cells compared with BBR. Treatment with B10 (1, 2 μM) induced apoptosis of A549 cells. Further investigations showed that B10 treatment dose-dependently affected mitochondrial functions, including oxygen consumption rate (OCR), mitochondrial membrane potential (MMP) and the morphology of mitochondria in A549 cells. Therefore, this work offers a new way for BBR structural modification through improving cell membrane permeability to affect mitochondrial functions and potential anti-tumor therapy in the future.
- Liu, Yi,Zhu, Ke-xin,Cao, Lei,Xie, Zhi-fu,Gu, Min,Lü, Wei,Li, Jing-ya,Nan, Fa-jun
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- Antimicrobial Activity of 9-O-Acyl- and 9-O-Alkylberberrubine Derivatives
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For the structure-activity relationship study on berberrubine derivatives, a series of compounds bearing 9-O-acyl- and 9-O-alkyl-substituents were synthesized and tested for antimicrobial activity against Gram-positive, Gram-negative bacteria and fungi. O
- Kim, Sung Han,Lee, Sang Jun,Lee, Joo Hyoung,Sun, Won Suck,Kim, Jung Han
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- Resonance driven regioselective demethylation of berberine. Microwave assisted synthesis of berberrubine and its assessment as fluorescent chemosensor for alkanes
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Abstract Berberrubine has been synthesized by microwave assisted selective demethylation of berberine. The high selectivity observed in this reaction has been explained and justified by means of computational calculations using Density Functional Theory (DFT) and Natural Resonance Theory (NRT). The existence of two resonant structures of berberrubine is the driving force of regioselective demethylation. Berberrubine is a chemosensor of alkanes, and may have practical applications in petrochemical analysis as a 'mass' detector because fluorescent response of saturated hydrocarbons does not depend on hydrocarbon chain length. Berberrubine operates via dipole-induced dipole interactions. Likewise, it has two fluorescent forms in acidic and basic media, which correspond to a keto-enol tautomerism. The fluorescent signal for berberrubine and the amplification of berberrubine-alkane signals by heating can be rationalized from the predominance of enol form when berberrubine is adsorbed onto silica gel.
- Delgado-Camón, Arantzazu,Jarne, Carmen,Cebolla, Vicente L.,Larra?aga, Olatz,De Cózar, Abel,Cossío, Fernando P.,Vara, Yosu,Domínguez, Andrés,Membrado, Luis,Galbán, Javier,Garriga, Rosa
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- A class of intestinal lysis type co-drugs and their preparation and use
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The present invention relates to a class of intestinal cleavage type co-drugs (Codrug) and preparation and use thereof, in particular, the present invention provides a co-drug compound as shown in formula I. The present invention further provides a method
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Paragraph 0150-0151; 0181-0184
(2022/01/20)
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- Ferrocene-berberine/indometacin@glucose oxidase@hyaluronic acid nano-drug as well as preparation method and application thereof
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The invention discloses a method for preparing a ferrocene-berberine/indomethacin@glucose oxidase@hyaluronic acid self-assembled targeting anti-cancer nano-drug, which comprises the following steps: designing ferrocene-berberine coupled drug molecules, inducing glucose oxidase self-assembly together with indomethacin, and wrapping with hyaluronic acid to obtain the anti-cancer nano-drug. The invention provides a preparation method of the ferrocene-berberine/indometacin@glucose oxidase@hyaluronic acid nano-drug and application thereof in cancer treatment. The nano-drug provided by the invention can be delivered in a targeted manner, and shows remarkable growth and transfer inhibition effects on liver cancer cells.
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Paragraph 0038-0039
(2021/04/14)
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- Camptothecin-berberine/indocyanine green nano-drug, preparation method and application
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The invention discloses a preparation method of a camptothecin-berberine/indocyanine green co-assembled mitochondrial-targeting micro-environment-response anti-cancer nano-drug. Camptothecin-berberinecoupled drug molecules containing a disulfide bond are designed, and are co-assembled with a photosensitizer indocyanine green to obtain the anti-cancer nano-drug. The camptothecin-berberine/indocyanine green co-assembled nano-drug provided by the invention is sensitive in tumor microenvironment response, can realize targeted drug delivery of cancer cell mitochondria, and improves the treatment effect of the drug on lung cancer through the synergistic effect of chemotherapy and photothermal therapy.
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Paragraph 0046-0047
(2020/07/15)
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- Dual-channel berberine-based fluorescent probe for detecting Hg/ClO as well as preparation method and application thereof
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The invention discloses a dual-channel berberine-based fluorescent probe for detecting Hg/ClO as well as a preparation method and application of the dual-channel berberine-based fluorescent probe. According to the invention, berberine is used as a raw material to prepare the dual-channel berberine fluorescent probe for detection of Hg/ClO. Berberine hydrochloride 1 is subjected to methoxy and chloride ion removal to obtain a ketone compound 2; the compound 2 is acidified and isomerized to obtain a phenolic compound 3; Duff formylation reaction is carried out on the compound 3 toobtain a p-hydroxy aldehyde compound 4; and the compound 4 and thiosemicarbazide are condensed to obtain a thiosemicarbazide Schiff base compound 5. The compound 5 can specifically recognize Hg and ClO, and the probe emits orange red fluorescence in the presence of Hg under the irradiation of 365nm ultraviolet light. In the presence of ClO, the probe emits green fluorescence, and inthe presence of other anions and metal ions, fluorescence does not occur. Therefore, the compound 5 can be used as a dual-channel fluorescent probe and has good application value.
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Paragraph 0026-0030
(2020/07/06)
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- Taxol-berberine nanodrug synthesis method and application
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The invention discloses a taxol-berberine nanodrug synthesis method, which realizes self-assembly of coupling drugs by designing a taxol-berberine coupling drug molecule containing disulfide bonds to obtain an anticancer nanodrug. The paclitaxel-berberine
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Paragraph 0044-0046
(2019/10/04)
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- Synthesis and use of 9-O-aryl substituted berberine derivatives
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The invention provides a novel method for synthesizing a 9-O-aryl substituted berberine derivative 5 and a 9-O-phenyl bridged berberine dimer 7. The method comprises the steps: removing methyl of a site 9 from berberine 1, which serves as a raw material, so as to obtain berberrubine 2, and subjecting the berberrubine 2 to protonation and reduction, so as to prepare tetrahydro berberrubine 3; subjecting the tetrahydro berberrubine 3 and iodo aromatic hydrocarbon to a C-O cross-coupling reaction under nitrogen protection so as to obtain a product 4, and then, carrying out oxidation, so as to obtain the target 9-O-aryl substituted berberine derivative 5; coupling the tetrahydro berberrubine 3 and 4o, and carrying out oxidation, thereby obtaining the berberine dimer 7. The berberine derivatives synthesized by the method have the advantages of good fat solubility, simple preparation method, high yield and the like. Discovered by in-vitro experiments, this kind of berberine derivatives havea relatively good inhibiting action on staphylococcus aureus, thereby having a potential application value in the field of antibacterial drugs.
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Paragraph 0052-0055
(2019/02/03)
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- Design, synthesis and anti-inflammatory effects of novel 9-O-substituted-berberine derivatives
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Berberine, an isoquinoline alkaloid in many medicinal herbs, has been found to possess broad pharmacological activities. A series of novel C-9-O-substituted-berberine derivatives have been synthesized and their anti-inflammatory effects evaluated both in vitro and in vivo. Compared to berberine, the new synthetic berberine derivatives 3i and 5e exhibit significantly improved inhibitory activities against the release of NO, TNF-α and IL-6. Furthermore, derivatives 3i and 5e were found to inhibit more effectively the migration of neutrophils and primitive macrophage in transgenic zebrafish larvae with injury-provoked inflammation. Pre-treatment with derivatives 3i or 5e could lead to a concentration-dependent decrease in nuclear factor-κB (NF-κB) p65 and NF-κB inhibitor α (IκBα) phosphorylation and inducible nitric oxide synthase (iNOS) expression in lipopolysaccharide (LPS)-induced RAW264.7 cells, which suggested that the anti-inflammatory activities of berberine derivatives 3i and 5e are related to their suppression of the NF-κB signal pathway.
- Huang, Mei-Yan,Lin, Jing,Huang, Zhi-Jian,Xu, Hong-Gui,Hong, Juan,Sun, Ping-Hua,Guo, Jia-Liang,Chen, Wei-Min
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p. 658 - 666
(2016/05/19)
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- Synthesis of berberine bromide analogs containing tertiary amides of acetic acid in the 9-O-position
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9-O-Acetamide analogs of berberine bromide were prepared in 20-87% yields via reaction of the isoquinoline alkaloid berberrubine with tertiary amides of bromoacetic acid. Aminolysis did not occur during reaction of methyl-2-(9-demethoxyberberine bromide-9-yl)hydroxyacetate with secondary amines. The corresponding acid or its ethyl ester was isolated.
- Nechepurenko,Komarova,Vasil'ev,Salakhutdinov
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p. 1047 - 1053
(2013/04/23)
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- Synthesis and biological evaluation of berberine-thiophenyl hybrids as multi-functional agents: Inhibition of acetylcholinesterase, butyrylcholinesterase, and Aβ aggregation and antioxidant activity
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A series of berberine-thiophenyl hybrids were designed, synthesised, and evaluated as inhibitors of acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) and β-amyloid (Aβ) aggregation and as antioxidants. Among these hybrids, compounds 4f and 4i, berberine linked with o-methylthiophenyl and o-chlorothiophenyl by a 2-carbon spacer, were observed to be potent inhibitors of AChE, with IC50 values of 0.077 and 0.042 μM, respectively. Of the tested compounds, 4i was also the most potent inhibitor of BuChE, with an IC50 value of 0.662 μM. Kinetic studies and molecular modelling simulations of the AChE-inhibitor complex indicated that a mixed-competitive binding mode existed for these berberine derivatives. The biological studies also demonstrated that these hybrids displayed interesting activities, including Aβ aggregation inhibition and antioxidant properties.
- Su, Tao,Xie, Shishun,Wei, Hui,Yan, Jun,Huang, Ling,Li, Xingshu
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p. 5830 - 5840
(2013/09/12)
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- Synthesis and structure-activity relationship of berberine analogues in LDLR up-regulation and AMPK activation
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Currently there is no approved medicine for the treatment of metabolic syndrome. A series of new derivatives of berberine (BBR) or pseudoberberine (1) was synthesized and evaluated for their activity on AMP-activated protein kinase (AMPK) activation and up-regulatory low-density-lipoprotein receptor (LDLR) gene expression, respectively. In addition, the four major metabolites of BBR in vivo were also examined for their activity on AMPK in order to further understand the chemical mechanisms responsible for its glucose-lowering efficacy. Among those BBR analogues, compound 1 exhibited the potential effect on AMPK activation and LDLR up-regulation as compared with BBR. The results suggested that compound 1 might be a multiple-target agent for the treatment of metabolic syndrome, and thus was selected as a promising drug candidate for further development.
- Wang, Yan-Xiang,Kong, Wei-Jia,Li, Ying-Hong,Tang, Sheng,Li, Zheng,Li, Yang-Biao,Shan, Yong-Qiang,Bi, Chong-Wen,Jiang, Jian-Dong,Song, Dan-Qing
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p. 6552 - 6558
(2013/01/15)
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- Benzenediol-berberine hybrids: Multifunctional agents for Alzheimer's disease
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We designed and synthesized a series of hybrid molecules, in an effort to identify novel multifunctional drug candidates for Alzheimer's disease (AD), by reacting berberine with benzenediol, melatonin, and ferulic acid. The products were evaluated for: (i
- Jiang, Huailei,Wang, Xu,Huang, Ling,Luo, Zonghua,Su, Tao,Ding, Ke,Li, Xingshu
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scheme or table
p. 7228 - 7235
(2012/01/14)
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- Synthesis, biological evaluation, and molecular modeling of berberine derivatives as potent acetylcholinesterase inhibitors
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By targeting the dual active sites of acetylcholinesterase (AChE), a new series of berberine derivatives was designed, synthesized, and evaluated as AChE inhibitors. Most of the derivatives inhibited AChE in the sub-micromolar range. Compound 8c, berberine linked with phenol by a 4-carbon spacer, showed the most potent inhibition of AChE. A kinetic study of AChE and BuChE indicated that a mix-competitive binding mode existed for these berberine derivatives. Molecular modeling studies confirmed that these hybrids target both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. This is the first report where AChE inhibitory activity has been associated with berberine as a lead molecule.
- Huang, Ling,Shi, Anding,He, Feng,Li, Xingshu
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experimental part
p. 1244 - 1251
(2010/05/02)
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- Synthesis and biological evaluation of a new series of berberine derivatives as dual inhibitors of acetylcholinesterase and butyrylcholinesterase
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A series of novel berberine derivatives were designed, synthesized, and biologically evaluated as inhibitors of both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Among these derivatives, compound 48a, berberine linked with 3-methylpyridi
- Huang, Ling,Luo, Zonghua,He, Feng,Lu, Jing,Li, Xingshu
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scheme or table
p. 4475 - 4484
(2010/08/22)
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