- Synthesis of new dihydroberberine and tetrahydroberberine analogues and evaluation of their antiproliferative activity on NCI-H1975 cells
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Dihydroberberine (DHBER), the partially reduced form of the alkaloid berberine (BER), is known to exhibit important biological activities. Despite this fact, there have been only few studies that concern the biological properties of functionalized DHBER.
- Benedetti, Serena,De Crescentini, Lucia,Mantellini, Fabio,Mari, Giacomo,Palma, Francesco,Santeusanio, Stefania
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- Dihydroberberine, a hydrogenated derivative of berberine firstly identified in Phellodendri Chinese Cortex, exerts anti-inflammatory effect via dual modulation of NF-κB and MAPK signaling pathways
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Dihydroberberine (DHB), a hydrogenated derivative of berberine (BBR), has been firstly identified in Phellodendri Chinese Cortex (PC) by HPLC-ESI-MS/MS. Nowadays most researches on PC focus on its main components like BBR, however, the role of its naturally-occurring derivatives remains poorly defined heretofore. The present work aimed to comparatively evaluate the in vivo anti-inflammatory properties and mechanisms of DHB and BBR in three typical inflammatory murine models. The results showed that DHB effectively mitigated acetic acid-induced vascular permeability, xylene-elicited ear edema and carrageenan-caused paw edema. Meanwhile, DHB markedly attenuated the inflammatory cell infiltration in pathological sections of ears and paws. DHB was also observed to significantly decrease the production and mRNA expression levels of IL-6, IL-1β, TNF-α, NO (iNOS) and PGE2 (COX-2), increase the release of IL-10, and inhibit the activation of NF-κB and MAPK signaling pathways. The anti-inflammatory effect of DHB was weaker than that of BBR. The results might further contribute to unraveling the pharmacodynamic basis of PC and support its ethnomedical use in the treatment of inflammatory diseases. DHB possesses good potential to be further developed into a promising anti-inflammatory alternative, and can serve as a lead template for novel anti-inflammatory candidate.
- Tan,Wang, Yongfu,Ai, Gaoxiang,Luo, Chaodan,Chen, Hanbin,Li, Cailan,Zeng, Huifang,Xie, Jianhui,Chen, Jiannan,Su
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- A new fluorescent probe for sensing of biothiols and screening of acetylcholinesterase inhibitors
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A new N2O-type BODIPY probe (LF-Bop) has been proposed for the selective and sensitive detection of biologically relevant small molecular thiols. This detection is based on the Michael addition reaction between the thiol and nitrostyrene groups in the probe, which decreases the quenching effect from the nitro group, thus resulting in the recovery of the deep-red fluorescence from the BODIPY structure. The results show that LF-Bop is able to detect all tested free thiols through a fluorescence turn-on assay. The lowest limit of detection (LOD) for glutathione was found to be down to nanomolar levels (220 nM). Based on this probe, we have developed a new fluorescence assay for the screening of acetylcholinesterase inhibitors. In total, 11 natural and synthetic alkaloids have been evaluated. Both experimental measurements and theoretical molecular docking results reveal that both natural berberine and its synthetic derivative dihydroberberine are potential inhibitors of acetylcholinesterase.
- Deng, Tao,Hu, Shiyou,Huang, Xin-An,Li, Yuge,Ling, Yanwu,Liu, Fang,Peng, Guiyuan,Wang, Xiaojuan,Wu, Shengjun
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- Discovery of mitochondria-targeting berberine derivatives as the inhibitors of proliferation, invasion and migration against rat C6 and human U87 glioma cells
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This research aims to synthesize lipophilic berberine derivatives and evaluate their antiglioma effects on C6 and U87 cells. The introduction of substituents with various carbon chain lengths on C-13- or C-9-O-position of the berberine scaffold led to the discovery of several potent inhibitors against glioblastoma cells. Derivatives substituted with the carbon chains of moderate length (twelve carbons) displayed improved lipophilicity and the strongest inhibitory effects. Several compounds presented dose-dependent repression against proliferation (IC50, 1.12-6.12 μM) and blocked migration and invasion by over 60% at lower dose levels. Furthermore, preliminary research about the underlying mechanism for the enhanced antiglioma ability indicated that these analogues preferentially localized into mitochondria, inducing the up-regulation of ROS production. Overall, these compounds represent promising candidates to combat glioblastoma and highlight new insight into the antiglioma therapy through interaction with mitochondria. This journal is
- Fu, Shengnan,Xie, Yanqi,Tuo, Jue,Wang, Yalong,Zhu, Wenbo,Wu, Sihan,Yan, Guangmei,Hu, Haiyan
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- Synthesis and structure of dihydroberberine nitroaryl derivatives – Potential ligands for G-quadruplexes
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(Figure Presented) A method was developed for the synthesis of dihydroberberine nitroaryl derivatives on the basis of dihydroberberine reactions with aromatic electrophiles (picryl chloride, 4-chloro-7-nitrobenzofurazan, 4-chloro-5,7-dinitrobenzofurazan, and 7-chloro-4,6-dinitrobenzofuroxan). The obtained 13-substituted dihydroberberine derivatives represent structures with significant intramolecular charge transfer and, according to the results of molecular docking analysis, can effectively bind with G-quadruplexes of telomeric DNA fragments.
- Burov, Oleg N.,Kurbatov, Sergey V.,Kletskii, Mikhail E.,Zagrebaev, Alexander D.,Mikhailov, Igor E.
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- Synthesis and evaluation of the antibacterial activities of 13‐substituted berberine derivatives
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The biological activities of berberine, a natural plant molecule, are known to be affected by structural modifications, mostly at position 9 and/or 13. A series of new 13‐substituted berberine derivatives were synthesized and evaluated in term of antimicrobial activity using various microorganisms associated to human diseases. Contrarily to the original molecule berberine, several derivatives were found strongly active in microbial sensitivity tests against Mycobacterium, Candida albicans and Gram‐positive bacteria, including na?ve or resistant Bacillus cereus, Staphylococcus aureus and Streptococcus pyogenes with minimal inhibitory concentration (MIC) of 3.12 to 6.25 μM. Among the various Gram‐negative strains tested, berberine’s derivatives were only found active on Helicobacter pylori and Vibrio alginolyticus (MIC values of 1.5–3.12 μM). Cytotoxicity assays performed on human cells showed that the antimicrobial berberine derivatives caused low toxicity resulting in good therapeutic index values. In addition, a mechanistic approach demonstrated that, contrarily to already known berberine derivatives causing either membrane permeabilization, DNA fragmentation or interacting with FtsZ protein, active derivatives described in this study act through inhibition of the synthesis of peptidoglycan or RNA. Overall, this study shows that these new berberine derivatives can be considered as potent and safe anti‐bacterial agents active on human pathogenic microorganisms, including ones resistant to conventional antibiotics.
- Olleik, Hamza,Yacoub, Taher,Hoffer, Laurent,Gnansounou, Senankpon Martial,Benhaiem‐henry, Kehna,Nicoletti, Cendrine,Mekhalfi, Malika,Pique, Valérie,Perrier, Josette,Hijazi, Akram,Baydoun, Elias,Raymond, Josette,Piccerelle, Philippe,Maresca, Marc,Robin, Maxime
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- Visualizing semipermeability of the cell membrane using a pH-responsive ratiometric AIEgen
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In clinical chemotherapy, some basic drugs cannot enter the hydrophobic cell membrane because of ionization in the acidic tumor microenvironment, a phenomenon known as ion trapping. In this study, we developed a method to visualize this ion trapping phenomenon by utilizing a pH-responsive ratiometric AIEgen, dihydro berberine (dhBBR). By observing the intracellular fluorescence ofdhBBR, we found that non-ionizeddhBBRcan enter cells more easily than ionized forms, which is in accordance with the concept of ion trapping. In addition,dhBBRshows superior anti-photobleaching ability toCurcuminthanks to its AIE properties. These results suggest thatdhBBRcan serve as a bioprobe for ion trapping.
- Gu, Yuan,Kwok, Ryan T. K.,Lam, Jacky W. Y.,Niu, Guangle,Tang, Ben Zhong,Wang, Yiming,Zhang, Han,Zhao, Zheng
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- Synthesis of 13-substituted derivatives of berberine: Aggregation-induced emission enhancement and pH sensitive property
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Five kinds of berberine derivatives with hydroxy, methyl, ethyl, benzyl and (4-methyl)benzyl group at 13-position have been synthesized and characterized. 13-hydroxyberberine chloride exhibits aggregation-induced emission enhancement (AIEE) property because of hydroxy group, which is beneficial to increase the rigidity of molecule by enlarging conjugated system. Optical properties in pure solution, CH3OH/H2O mixed solution, amorphous and crystalline state were comparatively investigated. Polymeric morphology and particle size of 13-hydroxyberberine chloride with different water fractions (0–90 vol%) were obtained by scanning electron microscope (SEM) and dynamic light scattering (DLS) method respectively, which provided reasonable explanation that the formation of small globular nanoparticles in mixed solution is conducive to the fluorescence emission. The single crystal structure of 13-hydroxyberberine chloride was determined by single-crystal X-ray diffraction. Crystallographic data indicated that the main mechanism of the AIEE phenomenon is the existences of J-aggregation (head to tail dipole stacking) combined with molecular planarization. The calculation done by DFT showed that the HOMO–LUMO bandgap is in accordance with experimental data. To further explore the biomedical application of 13-hydroxyberberine, its cell viability and cell imaging performance were examined, which demonstrate that 13-hydroxyberberine shows definite fluorescent intensity. In all, 13-hydroxyberberine should be a promising candidate for different biomedical application such as pH fluorescence probe because of its response to the stimuli of pH value.
- Tang, Xuemei,Zhang, Jianhui,Liu, Liyan,Yang, Depo,Wang, Huaqiao,He, Feng
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- Solution and Solid-State Analysis of Binding of 13-Substituted Berberine Analogues to Human Telomeric G-quadruplexes
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The interaction between 13-phenylalkyl and 13-diphenylalkyl berberine derivatives (NAX) and human telomeric DNA G4 structures has been investigated by both spectroscopic and crystallographic methods. NAX042 and NAX053 are the best compounds improving the performance of the natural precursor berberine. This finding is in agreement with the X-ray diffraction result for the NAX053-Tel12 adduct, showing the ligand which interacts via π-stacking, sandwiched at the interface of two symmetry-related quadruplex units, with its benzhydryl group contributing to the overall stability of the adduct by means of additional π-stacking interactions with the DNA residues. The berberine derivatives were also investigated for their cytotoxic activity towards a panel of human cancer cell lines. Compounds NAX042 and NAX053 affect the viability of cancer cell lines in a dose-dependent manner.
- Ferraroni, Marta,Bazzicalupi, Carla,Papi, Francesco,Fiorillo, Gaetano,Guamán-Ortiz, Luis Miguel,Nocentini, Alessio,Scovassi, Anna Ivana,Lombardi, Paolo,Gratteri, Paola
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- Synthesis and antibacterial evaluation of 13-substituted cycloberberine derivatives as a novel class of anti-MRSA agents
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A series of new 13-substituted cycloberberine (CBBR) derivatives were prepared and evaluated for their antibacterial activities against Gram-positive bacteria taking CBBR as the lead. Structure-activity relationship revealed that the introduction of a suitable electron-donating group at the 13-position in CBBR might be beneficial for the antibacterial potency. Among them, compounds 5b and 5w exhibited high potency against methicillin-sensitive (MSSA) and resistant strains of S. aureus (MRSA) with MIC values of 1–4 μg/mL. Both of them also displayed high stabilities in blood, and good in vivo safety profiles with LD50 values of 65.6 and 41.2 mg kg?1 in intravenous route respectively. Molecular docking analysis indicated that compound 5b might target FtsZ protein that could inhibit cell division, with the advantage of activity against multidrug resistant S. aureus. Therefore, we consider 13-substituted CBBR derivatives to be a novel class of anti-MRSA agents worthy of further investigation.
- Fan, Tian–Yun,Wang, Yan–Xiang,Tang, Sheng,Hu, Xin–Xin,Zen, Qing–Xuan,Pang, Jing,Yang, Yuan–Shuai,You, Xue–Fu,Song, Dan–Qing
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- Synthesis and anticancer activity of novel 9,13-disubstituted berberine derivatives
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Novel berberine derivatives with disubstituents on positions C9 and C13 were synthesized and evaluated for antiproliferative activities against human prostate cancer cell lines (PC3 and DU145), breast cancer cell line (MDA-MB-231) and human colon cancer cell lines (HT29 and HCT116). All compounds showed significantly enhanced antiproliferative activities compared with berberine. Notably, compound 18e exhibited the strongest cytotoxicity against PC3 cells with an IC50 value of 0.19 μM, and the highest selectivity index (SIPC3 > 20). Further studies showed that 18e could arrest the cell cycle at G1 phase, and significantly inhibit tumor cell colony forming and migration even at low concentrations. Interestingly, 18e could significantly induce cytoplasmic vacuolation, suggesting a different mode of action from berberine.
- Wang, Zhi-Cheng,Wang, Jing,Chen, Huang,Tang, Jie,Bian, Ai-Wu,Liu, Ting,Yu, Li-Fang,Yi, Zhengfang,Yang, Fan
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- Synthesis of new 13-diphenylalkyl analogues of berberine and elucidation of their base pair specificity and energetics of DNA binding
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A series of 13-diphenylalkyl berberine derivatives were designed and synthesized, and their base specificity and energetics of DNA binding were evaluated using one natural and two synthetic DNA polynucleotides. Biophysical evaluation demonstrated that the addition of the diphenylalkyl chain at the 13-position of berberine significantly improved the binding ability to DNA. The binding clearly revealed the high preference of the analogues to the alternating AT sequences compared to the alternating GC sequences. The binding affinity was enhanced with the increase in chain length up to a critical length of (CH 2)3 in all the cases, after which the binding affinity decreased. Analogue BR4 had the best affinity for DNA, which corresponds to a length of (CH2)3. The results also suggested the adenine-thymine (AT) base specificity of these berberine analogues and that the length of the side chain at the 13-position of the isoquinoline chromophore is critical in modulating the binding affinity.
- Bhowmik, Debipreeta,Buzzetti, Franco,Fiorillo, Gaetano,Orzi, Fabrizio,Syeda, Tanjia Monir,Lombardi, Paolo,Suresh Kumar, Gopinatha
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- Total Synthesis of (-)-Canadine, (-)-Rotundine, (-)-Sinactine, and (-)-Xylopinine Using a Last-Step Enantioselective Ir-Catalyzed Hydrogenation
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A concise asymmetric total synthesis of a group of tetrahydroprotoberberine alkaloids, (-)-canadine, (-)-rotundine, (-)-sinactine, and (-)-xylopinine, has been accomplished in three steps from the commercially available corresponding disubstituted phenylethylamine and disubstituted benzaldehyde. Our synthesis toward these four alkaloids took advantage of the following strategy: In the first step, we achieved an efficient and sustainable synthesis of secondary amine hydrochlorides via a fully continuous flow; in the second step, we developed a Pictet-Spengler reaction/Friedel-Crafts hydroxyalkylation/dehydration cascade for the construction of the dihydroprotoberberine core structure (ABCD-ring); and in the last step, Ir-catalyzed enantioselective hydrogenation was employed for the introduction of the desired stereochemistry at the C-14 position in the tetrahydroprotoberberine alkaloids. This work significantly expedites the asymmetric synthesis of the entire tetrahydroprotoberberine alkaloid family as well as a more diverse set of structurally related non-natural analogues.
- Chen, Fener,Chen, Wenchang,Chen, Yu,Jiang, Meifen,Li, Weijian,Tang, Pei,Yang, Zhi
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p. 8143 - 8153
(2021/06/28)
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- Method for preparing 5, 8-dihydro-6H-isoquinoline [3, 2-alpha] isoquinoline based on micro-reaction system
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The invention provides a method for preparing 5, 8-dihydro-6H-isoquinoline [3, 2-alpha] isoquinoline based on a micro-reaction system. A first solution and a second solution are introduced into a first micro-mixer through a feeding pump to be mixed; a mixture of an arylethylamine solution and an aryl aldehyde solution is pumped into a first fixed bed reactor through the first micro-mixer to be subjected to a dehydration condensation reaction; the mixture subjected to the dehydration condensation reaction is introduced into a second fixed bed reactor through a second micro-mixer for catalytic hydrogenation; the mixed material subjected to catalytic hydrogenation and a methanol solution of saturated hydrochloric acid are introduced into a micro-channel reactor through a third micro-mixer for a salt forming reaction, and vacuum concentration, pulping and purification are carried out to obtain secondary amine hydrochloride; and in the presence of acid, a dehydrating agent and an additive, the secondary amine hydrochloride and a glyoxal solution are subjected to Pictet-Spengler reaction and Friedel-Crafts hydroxyalkylation and dehydration cascade reaction, so as to obtain the 5, 8-dihydro-6H-isoquinoline [3, 2-alpha] isoquinoline compound.
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Paragraph 0119; 0134-0135; 0136; 0150-0151; 0152; 0166; ...
(2021/07/08)
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- Stereoselective Cycloaddition of Alkanesulfonyl Chlorides to Dihydroberberine
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Novel berberine derivatives with annelated four-membered sulfone rings were synthesized. Cycloaddition of alkanesulfonyl chlorides to dihydroberberine occurred with high stereoselectivity and formed a single stereoisomer.
- Gladkova,Luzina,Salakhutdinov
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p. 1062 - 1065
(2021/11/22)
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- Discovery of C-9 modified berberine derivatives as novel lipid-lowering agents
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Berberine (BBR), a kind of quaternary ammonium benzylisoquinoline alkaloids with multiple pharmacological activities, has been regarded as a promising lipid-lowering agent in the field of drug repurposing. Particularly, the chemical modification at the C-9 position of BBR can remarkably improve its lipid-lowering efficacy. In this study, thirteen novel BBR derivatives were rationally designed, synthesized, and evaluated by preliminary pharmacological tests. The results showed that most compounds exhibited more potent hypolipidemic activities when compared with BBR and simvastatin. Among these compounds, compound 2h-1 and 2h-2 exhibited better activity profiling in these four tests involving with inhibition of total cholesterol (TCHO), triglyceride (TG), and low-density lipoprotein cholesterol (LDLC) and the increase of high-density lipoprotein cholesterol (HDLC). Correspondingly, the BBR analogs with 9-O-cinnamic moiety probably exhibited potent lipid-lowering activity, and should be exploited as an important versatile template for the development of BBR-like lipid-lowering agents.
- Li, Dong-Dong,Yu, Pan,Xu, Hui,Wang, Zhen-Zhong,Xiao, Wei,Zhao, Lin-Guo
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- Synthesis and in vitro photocytotoxicity of 9-/13-lipophilic substituted berberine derivatives as potential anticancer agents
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The objective of this study was to synthesize the 9-/13-position substituted berberine derivatives and evaluate their cytotoxic and photocytotoxic effects against three human cancer cell lines. Among all the synthesized compounds, 9-O-dodecyl- (5e), 13-dodecyl- (6e), and 13-O-dodecyl-berberine (7e) exhibited stronger growth inhibition against three human cancer cell lines, (HepG2, HT-29 and BFTC905), in comparison with structurally related berberine (1). These three compounds also showed the photocytotoxicity in human cancer cells in a concentration-dependent and light dose-dependent manner. Through flow cytometry analysis, we found out a lipophilic group at the 9-/13-position of berberine may have facilitated its penetration into test cells and hence enhanced its photocytotoxicity on the human liver cancer cell HepG2. Further, in cell cycle analysis, 5e, 6e, and 7e induced HepG2 cells to arrest at the S phase and caused apoptosis upon irradiation. In addition, photodynamic treatment of berberine derivatives 5e, 6e, and 7e again showed a significant photocytotoxic effects on HepG2 cells, induced remarkable cell apoptosis, greatly increased intracellular ROS level, and the loss of mitochondrial membrane potential. These results over and again confirmed that berberine derivatives 5e, 6e, and 7e greatly enhanced photocytotoxicity. Taken together, the test data led us to conclude that berberine derivatives with a dodecyl group at the 9-/13-position could be great candidates for the anti-liver cancer medicines developments.
- Lin, Hong-Jhih,Ho, Jinn-Hsuan,Tsai, Li-Chen,Yang, Fang-Yu,Yang, Ling-Ling,Kuo, Cheng-Deng,Chen, Lih-Geeng,Liu, Yi-Wen,Wu, Jin-Yi
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supporting information
(2020/02/18)
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- A SET OF MITOCHONDRIA-TARGETED COMPOUNDS
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Here are described SkQ compounds containing cations of various types: alkyl(triphenyl)phosphonium cation, quaternary ammonium cations, including pH -dependent and permanent cations of rhodamines, berberine and palmatine alkaloids.
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(2019/01/17)
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- Evolution and Antibacterial Evaluation of 8-Hydroxy-cycloberberine Derivatives as a Novel Family of Antibacterial Agents Against MRSA
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Twenty-five new derivatives of 8-hydroxycycloberberine (1) were synthesized and evaluated for their activities against Gram-positive bacteria, taking 1 as the lead. Part of them displayed satisfactory antibacterial activities against methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA), as well as vancomycin-intermediate Staphylococcus aureus (VISA). Especially, compound 15a displayed an excellent anti-MRSA activity with MICs (minimum inhibitory concentrations) of 0.25–0.5 μg/mL, better than that of 1. It also displayed high stability in liver microsomes and whole blood, and the LD50 value of over 65.6 mg·kg?1 in mice via intravenous route, suggesting a good druglike feature. The mode of action showed that 15a could effectively suppress topo IV-mediated decatenation activity at the concentration of 7.5 μg/mL, through binding a different active pocket of bacterial topo IV from quinolones. Taken together, the derivatives of 1 constituted a promising kind of anti-MRSA agents with a unique chemical scaffold and a specific biological mechanism, and compound 15a has been chosen for the next investigation.
- Yang, Yuan-Shuai,Wei, Wei,Hu, Xin-Xin,Tang, Sheng,Pang, Jing,You, Xue-Fu,Fan, Tian-Yun,Wang, Yan-Xiang,Song, Dan-Qing
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- A Unified Strategy for the Syntheses of the Isoquinolinium Alkaloids Berberine, Coptisine, and Jatrorrhizine
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Total syntheses of the antibacterial alkaloids berberine, coptisine, and jatrorrhizine have been achieved in four steps through a unified route. The key step of this strategy is an efficient intramolecular Friedel-Crafts alkoxyalkylation which, following oxidation, establishes the isoquinolinium core of these natural products. Herein, the design and development of this synthetic strategy, which has enabled the shortest and most efficient syntheses of these alkaloids reported to date, is described.
- Mori-Quiroz, Luis M.,Hedrick, Sidnee L.,De Los Santos, Andrew R.,Clift, Michael D.
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p. 4281 - 4284
(2018/07/29)
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- Cyclized berberine derivative as well as preparation method and application of cyclized berberine derivative
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The invention provides a cyclized berberine derivative as well as a preparation method and application of the cyclized berberine derivative. The compound has a structure as shown in a formula I, wherein a symbol as shown in the specification shows a single bond or double bonds; X is a negative ion; m is equal to 0 or 1; Q is N or N+; and R is OR1, NHR2 or oxo. The compound provided by the invention has excellent activity of resisting to gram-positive bacteria and particularly methicillin (vancomycin)-resistant staphylococcus aureus.
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Paragraph 0208; 0209; 0210
(2018/04/21)
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- Preparation method of dihydroberberine
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The invention provides a preparation method of dihydroberberine. The preparation method comprises the following steps: in the presence of a catalyst, performing catalytic transfer hydrogenation on a compound (described in the specification) and a hydrogen donor in a certain solvent to obtain the compound (described in the specification) dihydroberberine. In the method, the raw material, berberinesalt, is cheap and easily available; reaction conditions are mild, the selectivity is good, and the yield is high; and intermediates and products are purified by crystallization to avoid column chromatography. The method disclosed by the invention is simple and easy to operate, stable in process, easy to control, easy to treat after reaction, high in product yield, and high in purity, and can be used in industrial production economically and conveniently.
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Paragraph 0017
(2019/01/08)
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- Discovery and Development of 8-Substituted Cycloberberine Derivatives as Novel Antibacterial Agents against MRSA
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8-Acetoxycycloberberine (2) with a unique skeleton was first identified to display a potent activity profile against Gram-positive bacteria, especially methicillin-resistant S. aureus (MRSA) with minimum inhibitory concentration (MIC) values of 1-8 μg/mL, suggesting a possible novel mechanism of action against bacteria. Taking 2 as the lead, 23 new 8-substituted cycloberberine (CBBR) derivatives including ether, amine, and amide were synthesized and evaluated for their antibacterial effect. The structure-activity relationship revealed that the introduction of a suitable substituent at the 8-position could greatly enhance the potency against MRSA. Among them, compounds 5d and 9e demonstrated equally effective anti-MRSA potency as lead 2, with an advantage of having a more stable pharmacokinetics feature. A preliminary mechanism study indicated that compound 9e acted upon bacteria partly through catalyzing the cleavage of bacterial DNA. Therefore, we consider that 8-substituted CBBR derivatives constitute a promising class of antibacterial agents in the treatment of MRSA infections.
- Fan, Tianyun,Hu, Xinxin,Tang, Sheng,Liu, Xiaojia,Wang, Yanxiang,Deng, Hongbin,You, Xuefu,Jiang, Jiandong,Li, Yinghong,Song, Danqing
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supporting information
p. 484 - 489
(2018/05/14)
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- A General, Concise Strategy that Enables Collective Total Syntheses of over 50 Protoberberine and Five Aporhoeadane Alkaloids within Four to Eight Steps
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A concise, catalytic, and general strategy that allowed efficient total syntheses of 22 natural 13-methylprotoberberines within four steps for each molecule is reported. This synthesis represents the most efficient and shortest route to date, featuring three catalytic processes: CuI-catalyzed redox-A3 reaction, Pd-catalyzed reductive carbocyclization, and PtO2-catalyzed hydrogenation. Importantly, this new strategy to the tetracyclic framework has also been applied to the collective concise syntheses of >30 natural protoberberines (without 13-methyl group) and five aporhoeadane alkaloids.
- Zhou, Shiqiang,Tong, Rongbiao
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p. 7084 - 7089
(2016/05/19)
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- Derivatives Of Protoberberine Biological Alkaloids And Use Of Same Inhibiting Ulcerative Colitis
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Disclosed are derivatives of protoberberine biological alkaloids or physiologically acceptable salts thereof produced by means of a derivative reaction of a source material of biological alkaline quaternary ammonium salts of protoberberine alkaloids, a preparation method for same and pharmaceutical uses thereof. The derivatives of protoberberine biological alkaloids or the physiologically acceptable salts thereof show activity inhibiting ulcerative colitis and can be used in the preparation of drugs for same.
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Paragraph 0057; 0058
(2015/02/19)
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- USE AND PREPARATION METHOD OF BERBERINE COMPOUNDS
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A method of treating nervous system diseases associated with dopamine receptors comprising administering a patent in need a compound having a structure of general formula (I) or a pharmaceutical acceptable salt, hydrate, or solvate thereof in a pharmaceutically effective amount, and a method of making the compound having the structure of general formula (I) or a pharmaceutical acceptable salt, hydrate, or solvate thereof. The compound of formula (I) has multiple pharmacological functions such as the functions of activating opioid receptors and blocking dopamine D2 receptors, and has good physicochemical properties and oral bioavailability. General animal experiments show that such a compound has significant and long-lasting analgesic and calming effects and can be used to treat pain and other mental illnesses.
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Paragraph 0028-0030
(2015/06/24)
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- New 13-pyridinealkyl berberine analogues intercalate to DNA and induce apoptosis in HepG2 and MCF-7 cells through ROS mediated p53 dependent pathway: Biophysical, biochemical and molecular modeling studies
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A new series of 13-pyridinealkyl berberine analogues was synthesized and their DNA binding efficacy studied by employing spectroscopic, calorimetric and molecular modeling techniques. Analogues with more than one CH2 group showed better intercalative binding than berberine. The analogue with one CH2 group bound DNA weaker than berberine. The binding of the analogue with single CH2 group was entropy driven, while those with more than one CH2 group was favoured by both entropy and enthalpy changes. Higher salt concentration and temperature destabilized the binding. A larger contribution from non-polyelectrolytic forces to the Gibbs energy and the involvement of strong hydrophobic interactions were inferred. Molecular modeling pin pointed the specific binding site and the non-covalent interactions in the association. The best DNA binding analogue (BER5) inhibited the growth of hepatocellular and breast carcinoma most efficiently. It induced apoptosis in HepG2 and MCF-7 cells with externalization of phosphatidylserine and reactive oxygen species generation with accumulation of cells in the G0/G1 phase. Furthermore, up regulation of p53 and p21 indicated the role of p53 in BER5 mediated apoptosis. The results suggested that 13-pyridinealkyl berberine analogues intercalated to DNA much stronger than berberine, the chain length of the linker plays an important role for the binding, and they induced ROS mediated apoptosis in HepG2 and MCF-7 cells by p53 modulation.
- Chatterjee, Sabyasachi,Mallick, Sumana,Buzzetti, Franco,Fiorillo, Gaetano,Syeda, Tanjia Monir,Lombardi, Paolo,Saha, Krishna Das,Kumar, Gopinatha Suresh
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p. 90632 - 90644
(2015/11/11)
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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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p. 916 - 922
(2015/12/26)
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- DERIVATIVES OF PROTOBERBERINE BIOLOGICAL ALKALOIDS AND USE OF SAME INHIBITING ULCERATIVE COLITIS
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Disclosed are derivatives of protoberberine biological alkaloids or physiologically acceptable salts thereof produced by means of a derivative reaction of a source material of biological alkaline quaternary ammonium salts of protoberberine alkaloids, a preparation method for same and pharmaceutical uses thereof. The derivatives of protoberberine biological alkaloids or the physiologically acceptable salts thereof show activity inhibiting ulcerative colitis and can be used in the preparation of drugs for same.
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Paragraph 0041
(2014/10/28)
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- Structural optimization of berberine as a synergist to restore antifungal activity of fluconazole against drug-resistant Candida albicans
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We have conducted systematic structural modification, deconstruction, and reconstruction of the berberine core with the aim of lowering its cytotoxicity, investigating its pharmacophore, and ultimately, seeking novel synergistic agents to restore the effectiveness of fluconazole against fluconazole-resistant Candida albicans. A structure-activity relationship study of 95 analogues led us to identify the novel scaffold of N-(2-(benzo[d][1,3]dioxol-5-yl)ethyl)-2- (substituted phenyl)acetamides 7 a-l, which exhibited remarkable levels of in vitro synergistic antifungal activity. Compound 7 d (N-(2-(benzo[d][1,3]dioxol- 5-yl)ethyl)-2-(2-fluorophenyl)acetamide) significantly decreased the MIC 80 values of fluconazole from 128.0 μg mL-1 to 0.5 μg mL-1 against fluconazole-resistant C. albicans and exhibited much lower levels of cytotoxicity than berberine toward human umbilical vein endothelial cells. Build it better: Structural optimization of berberine led to the identification of the novel scaffold of N-(2-(benzo[d][1,3]dioxol-5-yl) ethyl)-2-(substituted phenyl)acetamides 7 a-l, which exhibited remarkable in vitro synergistic antifungal activity against fluconazole-resistant Candida albicans in combination with fluconazole. Compound 7 d exhibited much lower cytotoxicity than berberine toward human umbilical vein endothelial cells. Copyright
- Liu, Hong,Wang, Liang,Li, Yan,Liu, Jiang,An, Maomao,Zhu, Shaolong,Cao, Yongbing,Jiang, Zhihui,Zhao, Mingzhu,Cai, Zhan,Dai, Li,Ni, Tingjunhong,Liu, Wei,Chen, Simin,Wei, Changqing,Zang, Chengxu,Tian, Shujuan,Yang, Jingyu,Wu, Chunfu,Zhang, Dazhi,Liu, Hua,Jiang, Yuanying
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p. 207 - 216
(2014/01/17)
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- Discovery, synthesis and biological evaluation of cycloprotoberberine derivatives as potential antitumor agents
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A series of new 1,13-cycloprotoberberine derivatives defined through variations at the 9-position were designed, synthesized and evaluated for their cytotoxicities in human HepG2 (hepatoma), HT1080 (fibrosarcoma) and HCT116 (colon cancer) cells. The preliminary structure-activity relationship (SAR) revealed that the replacement of 9-methoxyl with an ester moiety might significantly enhance the antiproliferative activity in vitro. Notably, compound 7f demonstrated equipotent cytotoxicity activity against breast cancer MCF-7 (parent) and doxorubicin (DOX)-resistant MCF-7 (MCF-7/ADrR) cells, indicating a mode of action different from that of DOX. Further mechanism study showed that 7f significantly inhibited activity of DNA topoisomerase I (Top I) and Top II. G2/M phase arrest and tumor cell growth reduction was observed thereafter. Thus, we consider cycloprotoberberine analogues to be a new family of promising antitumor agents with an advantage of inhibiting drug-resistant cancer cells.
- Li, Yang-Biao,Zhao, Wu-Li,Wang, Yan-Xiang,Zhang, Cai-Xia,Jiang, Jian-Dong,Bi, Chong-Wen,Tang, Sheng,Chen, Ru-Xian,Shao, Rong-Guang,Song, Dan-Qing
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p. 463 - 472
(2013/10/01)
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- PHARMACEUTICAL SUBSTANCES ON THE BASIS OF MITOCHONDRIALLY ADDRESSED ANTIOXIDANTS
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This invention relates to the fields of pharmaceutics and medicine, and, in particular, relates to the production and use of pharmaceutical substances on the basis of mitochondria-addressed compounds. The invention discloses methods for synthesis, purification and storage of mitochondria-addressed antioxidants, making it possible to produce said substances in a form and quality meeting the demands made on active ingredients of medicinal preparations - the pharmaceutical substances. The invention also discloses methods for design and selection of new mitochondria-addressed antioxidants having specified properties.
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Page/Page column 22
(2012/10/07)
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- PHARMACEUTICAL SUBSTANCES ON THE BASIS OF MITOCHONDRIA-ADDRESSED ANTIOXIDANTS
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This invention relates to the fields of pharmaceutics and medicine, and, in particular, relates to the production and use of pharmaceutical substances on the basis of mitochondria-addressed compounds. The invention discloses methods for synthesis, purification and storage of mitochondria-addressed antioxidants, making it possible to produce said substances in a form and quality meeting the demands made on active ingredients of medicinal preparations—the pharmaceutical substances. The invention also discloses methods for design and selection of new mitochondria-addressed antioxidants having specified properties.
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Page/Page column 18-19
(2012/10/18)
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- Synthesis, structure-activity relationship and in vitro anti-mycobacterial evaluation of 13-n-octylberberine derivatives
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Twenty-eight new 13-n-octylberberine derivatives were synthesized and evaluated for their activities against drug-susceptible Mycobacterium tuberculosis (M. tuberculosis) strain H37Rv. Among these compounds, compound 16e was the most effective anti-tubercular agent with a MIC value of 0.125 μg/mL. Importantly, compound 16e exhibited more potent effect against rifampicin (RIF)- and isoniazid (INH)-resistant M. tuberculosis strains than both RIF and INH, suggesting a new mechanism of action. Therefore, it has been selected as a drug candidate for further investigation, or as a chemical probe for identifying protein target and studying tuberculosis biology. We consider 13-n-octylberberine analogs to be a promising novel class of antituberculars against multi-drug-resistant (MDR) strains of M. tuberculosis.
- Liu, Yan-Xin,Xiao, Chun-Ling,Wang, Yan-Xiang,Li, Ying-Hong,Yang, Yan-Hui,Li, Yang-Biao,Bi, Chong-Wen,Gao, Li-Mei,Jiang, Jian-Dong,Song, Dan-Qing
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experimental part
p. 151 - 158
(2012/07/17)
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- Benzoquinolizinium salt derivatives as anticancer agents
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13-substituted 5,6-dihydrodibenzo[a,g]quinolizinium salt compounds of the general formula (I): processes for the preparation of said compounds, pharmaceutical compositions containing said compounds and the use of said compounds for the manufacture of medicaments suitable for the treatment of cancerous diseases.
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Page/Page column 10-11
(2011/02/18)
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- Improved enamine-type addition of dehydroaporphine using microwave irradiation
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Previous report demonstrated that 7-substituted aporphine, possessing interesting biological aspects, could be synthesized via an enamine-type addition of dehydroaporphine reacted with an electrophile, but it has the drawbacks of a long reaction time, low yield, and limitation to reactive electrophiles. Here we found that the reaction time and yield could greatly be improved under microwave irradiation in the presence of 4 equiv of sodium iodide for the synthesis of 7-benzyl dehydroglaucine. The application of this finding for treating dehydroglaucine with a variety of alkyl bromides also gave corresponding 7-substituted dehydroglaucines (2a-j) with yields of 14-89%. Other enamines such as 1,10-dimethoxydehydroaporphine (3a), 2,9-diacetyldehydroboldine (3b), and 7,8-dihydroberberine (5) were found to react with benzyl bromide under similar conditions as described above to give corresponding products (4a-b, 6) in satisfactory yields, indicating the versatility of this improved reaction condition.
- Huang, Wei-Jan,Huang, Chih-Chiang,Hsin, Ling-Wei,Tsai, Yeun-Min,Lin, Chin-Ting,Lin, Jung-Hsin,Lee, Shoei-Sheng
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body text
p. 3062 - 3064
(2010/08/05)
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- Synthesis and structure-activity relationships of novel, substituted 5,6-dihydrodibenzo[a,g]quinolizinium P2X7 antagonists
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Iminium quaternary protoberberine alkaloids (QPA) have been found to be novel P2X7 antagonists. To assess their structure-activity relationships, these compounds were modified at their R1 and R2 groups and assayed for their ability to inhibit the 2′(3′)-O-(4-benzoylbenzoyl)-ATP (BzATP)-induced uptake of fluorescent ethidium by HEK-293 cells stably expressing the human P2X7 receptor, and their ability to inhibit BzATP-induced IL-1β release by differentiated THP-1 cells. Compounds 15a and 15d, with alkyl groups at the R1 position, and especially compound 19h, with the 2-NO2-4,5-dimethoxy-benzyl group at the R2 position, had potent inhibitory efficacy as P2X7 antagonists.
- Lee, Ga Eun,Lee, Ho-Sung,Lee, So Deok,Kim, Jung-Ho,Kim, Won-Ki,Kim, Yong-Chul
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scheme or table
p. 954 - 958
(2009/08/15)
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- Berberine analogues as a novel class of the low-density-lipoprotein receptor up-regulators: Synthesis, structure-activity relationships, and cholesterol-lowering efficacy
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Twenty-nine derivatives of berberine (1) or pseudoberberine (2) were designed, semisynthesized, and evaluated for their up-regulatory activity on the low-density-lipoprotein receptor (LDLR) expression. SAR analysis revealed that (i) the methylenedioxy group at the 2- and 3-position is an essential element to keep the activity, (ii) the 7-position quaternary ammonium and planar structure of the compound are activity-required, and (iii) addition of electron-donating groups at the 7- or 13-position reduced the activity. Of the compound 1 analogues, compound 2 exhibited an increased activity on LDLR expression compared to 1.Inthe hyperlipidemic rats, compound 2 (100 (mg/kg)/day) reduced blood CHO and LDL-c by 42.6% and 49.4%, respectively, more efficient than 1 did (p 50 of 2 in mice was over 5000 mg/kg (oral). We consider compound 2 a promising cholesterol- lowering drug candidate.
- Li, Ying-Hong,Yang, Peng,Kong, Wei-Jia,Wang, Yan-Xiang,Hu, Chang-Qin,Zuo, Zeng-Yan,Wang, Yue-Ming,Gao, Hong,Gao, Li-Mei,Feng, Yan-Chun,Du, Na-Na,Liu, Ying,Song, Dan-Qing,Jiang, Jian-Dong
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experimental part
p. 492 - 501
(2009/09/25)
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- PHARMACEUTICALLY AVAILABLE PROTOBERBERINE SALTS DERIVATIVES, AND PROTOBERBERINE DERIVATIVES AND SALTS THEREOF
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The antifungal formulation comprising the novel compounds of the following chemical formulae (I) and (II) exhibit in vitro antifungal activity against fungi including cutaneous filamentous fungus, such as Epidermophyton, Microsporum, Trichophyton, Sporothrix schenckii, Aspergillus or Candida. The formulation of the present invention exhibit in vitro antifungal activity at the concentration of 1-100 mu g/ml. wherein R1, R2, and R4 may be the same or different, and represent C1-C5 alkoxy, R3 represents hydrogen or C1-C10 alkyl, A- represents inorganic acid ion, organic acid ion or halide, R5 represents hydrogen, pyridylmethyl, substituted pyridylmethyl or a group having the following chemical formula(XI) wherein Z1, Z2, Z3, Z4 and Z5 may be the same or different and represent hydrogen, halogen, C1-C5 alkyl, trifluoromethyl, phenyl, substituted phenyl, nitro, C1-C4 alkoxy, C1-C4 alkylamino, acetylamino, C1-C8 trialkyl ammonium, guanidinyl, methylthio, ethylthio, trifluoromethoxy, hydroxy, phenoxy, vinyl, carboxyl and C1-C2 alkoxycarbonyl group.
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- Convenient synthesis of 2,3,9,10-tetraoxygenated protoberberine alkaloids and their 13-methyl alkaloids
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New and convenient synthesis of 2,3,9,10-tetraoxygenated protoberberine alkaloids and their 13-methyl alkaloids through the same intermediates was developed. Acylation of the brominated benzylphenethylamine (13) with α- chloro-α-(methylthio)acetyl chloride, followed by cyclization with stannic chloride, furnished the key intermediates 4-methylthio-3- phenethylisoquinolin-3-ones (14), which were methylated to provide their methyl derivatives (17). Both isoquinolin-3-ones (14, 17) were easily transformed into protoberberine alkaloids (16) and their 13-methyl alkaloids (21) in good yield.
- Hanaoka, Miyoji,Hirasawa, Taeko,Cho, Won Jea,Yasuda, Shingo
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p. 399 - 404
(2007/10/03)
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- The Polonovski-Potier reaction of berbine N-oxides. Synthesis of 8-hydroxymethyl and 8-methylberbines
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The Polonovski-Potier reaction of trans and cis berbines N-oxides was studied. The 8-cyano derivative obtained from trans N-oxides were used to synthesize 8-hydroxymethyl and 8-methyl berbines. This procedure was applied to the stereocontroled synthesis of (8R, 14S)-(-)-8-methylcanadine from (14S)-(-)-canadine. (C) 2000 Elsevier Science Ltd.
- Suau, Rafael,Nájera, Francisco,Rico, Rodrigo
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p. 9713 - 9723
(2007/10/03)
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- Antimicrobial activity of 8-alkyl- and 8-phenyl-substituted berberines and their 12-bromo derivatives
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The 8-alkyl- (3-6), 8-phenyl- (7), 12-bromo- (8), 8-alkyl-12-bromo- (9- 12), and 12-bromo-8-phenyl- (13) berberine derivatives were prepared and tested for their antimicrobial activity in vitro to evaluate structure- activity relationships. Introduction of the alkyl or phenyl group and the bromine atom into the C-8 and C-12 positions of berberine (1), respectively, led to significant increases of the antimicrobial activity. In both the 8- alkyl- and 8-alkyl-12-bromo-berberines (3-6 and 9-12, respectively), the antibacterial activity increased as the length of the aliphatic chain increased. The exception was the activity against Candida albicans and Escherichia coli, which did not always increase as the alkyl side chain lengthened. Among the compounds tested, 12-bromo-8-n-hexylberberine (12) was 64, 256, 128, 16, and 32 times more active against Staphylococcus aureus, Bacillus subtilis, Salmonella enteritidis, E. coli, and C. albicans, respectively, in comparison to the clinically used berberine. Compound 12 was also found to be 8, 16, and 128 times more active against S. aureus, S. enteritidis, and C. albicans, respectively, than kanamycin sulfate, but was of the same order of activity against B. subtilis, and only one-fourth as active against E. coli.
- Iwasa, Kinuko,Lee, Dong-Ung,Kang, So-Im,Wiegrebe, Wolfgang
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p. 1150 - 1153
(2007/10/03)
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- Re-examination of the synthesis of 7,8-dimethoxy-2-methyl-3-(4',5'-methylenedioxy-2'-vinylphenyl)isocarbos tyril
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Oxidation of the enamine (6) to the isocarbostyril (7) was re-examined. Simply stirring a dimethylformamide (DMF) solution of 6 provided 7 with good reproducibility, in the presence of KCN under an oxygen atmosphere. The structure of the chloroform adduct (8) was determined by an X-ray analysis.
- Ishii,Takeda,Ogata,Hanaoka,Harayama
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p. 2712 - 2714
(2007/10/02)
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- Improved delivery through biological membranes. XV. Sustained brain delivery of berberine
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The dihydropyridine: pyridinium salt redox system was extended to large molecules which contain pyridinium partial structures. By application of the system to a salient example, berberine, it was possible to deliver this antineoplastic agent to the brain as its corresponding dihydro derivative. Berberine itself does not enter the brain after systemic administration. After delivery and oxidation, berberine left the brain slowly (T 1/2 ? 11 hrs). Dihydroberberine was shown to be less toxic than berberine but significantly more effective in increasing the life span of mice inoculated intracerebrally with P388 lymphocytic leukemia cells.
- Bodor,Brewster
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p. 235 - 240
(2007/10/02)
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