15401-69-1Relevant articles and documents
Synthesis of Mannich base derivatives of berberine and evaluation of their anticancer and antioxidant effects
Mistry, Bhupendra,Patel, Rahul V.,Keum, Young Soo,Noorzai, Rafi,Gansukh, Enkhtaivan,Kim, Doo Hwan
, p. 73 - 77 (2016)
The 9-demethylated derivative of the isoquinoline alkaloid berberine was derivatised in its isoquinoline moiety using enamines derived from formaldehyde and morpholine, piperidine, carbazole and six variously substituted piperazines to form Mannich base products which were evaluated for their in vitro biological effects. Standard tests determined their radical scavenging potential and their ferric reducing antioxidant power (FRAP). Cancerous growth inhibitory efficacies were assessed using cervical cancer cell lines HeLa and CaSki and their cytotoxicities towards normal cell lines were evaluated using Madin-Darby canine kidney (MDCK) cell lines. Piperazine derivatives bearing a heterocyclic nitrogen substituent such as a pyridyl or a pyrimidyl ring were the most active antioxidant and anticancer agents. A carbazole moiety attached to the berberine core also demonstrated excellent inhibitory effects on cancerous cells.
Synthesis of berberine-piperazine conjugates as potential antioxidant and cytotoxic agents
Mistry, Bhupendra,Keum, Young Soo,Pandurangan, Muthuraman,Patel, Rahul V.,Kim, Doo Hwan
, p. 2461 - 2470 (2016)
Piperazine derivatives bearing different electron-withdrawing and electron-donating functional groups were linked to the well-known isoquinoline alkaloid derivative, berberine via efficient organic transformations. The entire target berberine-based analogues were examined for their in vitro antioxidant potency using 2,2-diphenyl-1-picrylhydrazyl and 2,2′-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid bioassays, and anticancer activities using sulforhodamine B assay against HeLa and CaSki cervical cancer cell lines in addition to the cytotoxicity using Madin-Darby canine kidney non-cancer cell lines and, ascorbic acid and berberine used as a control for antioxidant and anticancer activities, respectively. Bioassay results revealed that newer compounds were more active against CaSki and HeLa cell lines with therapeutic indices better than that of parent berberine and showed tolerable cytotoxicity to the normal cells. A final analogue 5a with 4-methylpiperazine substituent indicated most significant anticancer potency with a therapeutic index of 58.53 (HeLa) and 48.76 (CaSki), followed by those bearing meta-chloropiperazine rings with a therapeutic index of 41.83 (HeLa) and 47.35 (CaSki), respectively.In addition, newly synthesized analogues exerted a significant radical scavenging activity against 2,2′-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid cation with IC50 values of 8.917 μg/mL, and were good to moderate scavengers of 2,2-diphenyl-1-picrylhydrazyl radical with IC50 values of 25.40 μg/mL. Synthesized compound was characterized using several techniques, fourier transform infrared spectroscopy, 1H nuclear magnetic resonance, 13C nuclear magnetic resonance, mass spectroscopy and elemental (CHN) analyses.
Berberine and its metabolites: Relationship between physicochemical properties and plasma levels after administration to human subjects
Spinozzi, Silvia,Colliva, Carolina,Camborata, Cecilia,Roberti, Marinella,Ianni, Cristina,Neri, Flavia,Calvarese, Claudio,Lisotti, Andrea,Mazzella, Giuseppe,Roda, Aldo
, p. 766 - 772 (2014)
Berberine (1) is an alkaloid used widely in the treatment of several diseases. However, its physicochemical properties, pharmacokinetics, and metabolism remain unclear, and conflicting data have been reported. In this study, the main physicochemical properties of 1 and its metabolites were evaluated, including lipophilicity, solubility, pKa, and albumin binding. A sensitive HPLC-ESIMS/MS method was developed and validated to identify 1 and its main metabolites in human plasma. This method was used to quantify their levels in the plasma of healthy volunteers and hypercholesterolemic patients following a single dose and chronic administration, respectively. In both cases, berberrubine (2) was found to be the main metabolite. Surprisingly, 2 is more lipophilic than 1, which suggests that this compound tautomerizes to a highly conjugated, electroneutral quinoid structure. This was confirmed by NMR studies. These results indicate that the higher plasma concentration of 2 was a consequence of a more efficient intestinal absorption, suggesting that berberrubine is potentially more pharmacologically active than berberine.
Discovery of 2-aminothiazolyl berberine derivatives as effectively antibacterial agents toward clinically drug-resistant Gram-negative Acinetobacter baumanii
Gao, Wei-Wei,Gopala, Lavanya,Bheemanaboina, Rammohan R. Yadav,Zhang, Guo-Biao,Li, Shuo,Zhou, Cheng-He
, p. 15 - 37 (2018)
Aminothiazolyl berberine derivatives as potentially antimicrobial agents were designed and synthesized in an effort to overcome drug resistance. The antimicrobial assay revealed that some target compounds exhibited significantly inhibitory efficiencies toward bacteria and fungi including drug-resistant pathogens, and the aminothiazole and Schiff base moieties were helpful structural fragments for aqueous solubility and antibacterial activity. Especially, aminothiazolyl 9-hexyl berberine 9c and 2,4-dichlorobenzyl derivative 18a exhibited good activities (MIC = 2 nmol/mL) against clinically drug-resistant Gram-negative Acinetobacter baumanii with low cytotoxicity to hepatocyte LO2 cells, rapidly bactericidal effects and quite slow development of bacterial resistance toward A. baumanii. Molecular modeling indicated that compounds 9c and 18a could bind with GLY-102, ARG-136 and/or ALA-100 residues of DNA gyrase through hydrogen bonds. It was found that compounds 9c and 18a were able to disturb the drug-resistant A. baumanii membrane effectively, and molecule 9c could not only intercalate but also cleave bacterial DNA isolated from resistant A. baumanii, which might be the preliminary antibacterial action mechanism of inhibiting the growth of A. baumanii strain. In particular, the combination use of compound 9c with norfloxacin could enhance the antibacterial activity, broaden antibacterial spectrum and overcome the drug resistance.
Discovery of natural berberine-derived nitroimidazoles as potentially multi-targeting agents against drug-resistant Escherichia coli
Zhang, Guo-Biao,Maddili, Swetha Kameswari,Tangadanchu, Vijai Kumar Reddy,Gopala, Lavanya,Gao, Wei-Wei,Cai, Gui-Xin,Zhou, Cheng-He
, p. 557 - 568 (2018)
A series of natural berberine-derived nitroimidazoles as novel antibacterial agents were designed, synthesized and characterized by nuclear magnetic resonance (NMR), infrared spectra (IR), and high resolution mass spectra (HRMS) spectra. The antimicrobial evaluation showed that some target molecules exhibited moderate to good inhibitory activities against the tested bacteria and fungi including clinical drug-resistant strains isolated from infected patients. Especially, 2-fluorobenzyl derivative 8f not only gave strong activity against drug-resistant E. coli with the minimal inhibitory concentration (MIC) value of 0.003 mM, 33-fold more active than norfloxacin, but also exhibited low toxicity toward RAW 264.7 cells and less propensity to trigger resistance. The aqueous solubility and ClogP values of target compounds were investigated to elucidate the structureactivity relationships. Molecular docking and quantum chemical studies for compound 8f rationally explained its antibacterial effect. The further exploration of antibacterial mechanism revealed that the highly active compound 8f could effectively permeabilize E. coli cell membrane and intercalate into DNA isolated from resistant E. coli to form 8f-DNA complex that might block DNA replication to exert the powerful bioactivities. Compound 8f could also selectively address resistant E. coli from a mixture of various strains.
Synthesis, antioxidant and anticancer screenings of berberine-indole conjugates
Mistry, Bhupendra,Keum, Young-Soo,Kim, Doo Hwan
, p. 3241 - 3256 (2016)
A variety of heterocyclic nitrogen cores in the form of indole moieties were linked to the natural isoquinoline alkaloid molecule berberine to achieve anticipated antioxidant and anticancer properties. An efficient synthetic pathway afforded final compounds 5a-j, which were tested in vitro for antioxidant potency using 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt radical (ABTS) bioassays, and for anticancer activity using sulforhodamine B (SRB) assay against HeLa and Caski cancer cell lines. Moreover, the toxic nature of the resultant molecules was investigated using Madin-Darby canine kidney cells. The therapeutic indices of 5a-j were more appreciable against the Caski than HeLa cell line, in which compounds with electron-releasing alkyl or alkoxy functional group on indole entity as well as azaindole derivative performed well. In addition, these compounds were well endowed with antioxidant properties, in addition to the equal antioxidant effect of the compound with electron-withdrawing chlorine atom within indole entity. Adequate confirmation of the structure of the final analogues was achieved using Fourier-transform infrared (FT-IR), 1H nuclear magnetic resonance (NMR), and mass spectroscopy and elemental (CHN) analysis.
Synthesis and anticancer activity of a novel series of 9-O-substituted berberine derivatives: A lipophilic substitute role
Lo, Chih-Yu,Hsu, Lin-Chen,Chen, Min-Shin,Lin, Yi-Jing,Chen, Lih-Geeng,Kuo, Cheng-Deng,Wu, Jin-Yi
, p. 305 - 309 (2013)
To alter its hydrophobicity, a series of compounds bearing 9-O-alkyl- or 9-O-terpenyl- substituted berberine were synthesized and evaluated for anticancer activity against human cancer HepG2 and HT29 cell lines. We found that the lipophilic substitute of 9-O-alkyl- and 9-O-terpenyl berberine derivatives plays a role in inhibiting the human cancer cell growth and its activity could be maximized with the optimized substitute type and chain length. Most strikingly, nonetheless, of the six compounds prepared, sample 8, a farnesyl 9-O-substituted berberine, showed either comparable or better cytotoxic activity against human cancer HepG2 cell line than that of berberine. Compound 8 had also shown a 104-fold antiproliferation activity in compare with berberine against human hepatoma HepG2 cell lines after 48 incubation hours. Further, in Hoechst 33258 and annexin V-FITC/PI staining analyses it induced apoptosis in HepG2 cells at lower concentration than that of berberine for 24 h. Take all; farnesyl 9-O-substituted berberine could be a potential candidate for new anticancer drug development.
Synthesis, characterization, and biological evaluations of 1,3,5-triazine derivatives of metformin cyclization with berberine and magnolol in the presence of sodium methylate
Cao, Han,Liao, Shili,Zhong, Wenjing,Xiao, Xuerong,Zhu, Jiancheng,Li, Weimin,Wu, Xia,Feng, Yifan
, (2017)
The novel target products were synthesized in the formation of a triazine ring from berberine, magnolol, and metformin catalyzed by sodium methylate. The structures of products 1-3 were firstly confirmed by extensive spectroscopic analyses and single-crystal X-ray diffraction. The crystal structures of the target product 2 and the intermediate product 7b were reported for the first time. All target products were evaluated for their anti-inflammatory and antidiabetic activities against INS-1 and RAW264.1 cells in vitro and all products showed excellent anti-inflammatory effects and anti-insulin resistance effects. Our studies indicated that new compounds 1-3 were found to be active against inflammation and insulin resistance.
ANTIBACTERIAL ACTIVITY OF BEROLINE
Potapova, E. Yu.,Khaidarov, K. Kh.,Sadykov, Yu. D.
, p. 856 - 857 (1988)
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Experimental and quantum-chemical study of nucleophilic substitution mechanism in berberine
Burov, Oleg N.,Kletskii, Mikhail E.,Fedik, Nikita S.,Kurbatov, Sergey V.,Lisovin, Anton V.
, p. 997 - 1007 (2015)
Principal differences in the interaction mechanisms of alkaloid berberine with primary and secondary amines were investigated experimentally and by quantum-chemical calculations according to density functional theory (DFT/B3LYP) with 6-31G** basis set. The nucleophilic substitution of 9-metoxy group with primary amine was shown to proceed through a stage of σ-complex formation and led to 9-alkylamino derivatives of berberine. Analogous substitution with a secondary amine did not occur due to unfavorable thermodynamic parameters. The secondary amine participated in this reaction not as the attacking nucleophile, but rather as a bifunctional catalyst of berberine hydrolysis to berberrubine. The driving force for all these processes was the stabilization of products by hydrogen bonding. Based on the obtained results, we developed a new effective method for the preparation of berberrubine, one of the key intermediates in synthetic transformations of berberine. New 9-monoalkylamino derivatives of berberine containing indole moieties were synthesized.
Synthesis and evaluation of 9-O-substituted berberine derivatives containing aza-aromatic terminal group as highly selective telomeric G-quadruplex stabilizing ligands
Ma, Yan,Ou, Tian-Miao,Tan, Jia-Heng,Hou, Jin-Qiang,Huang, Shi-Liang,Gu, Lian-Quan,Huang, Zhi-Shu
, p. 3414 - 3417 (2009)
A series of new 9-O-substituted berberine derivatives (4a-j) as telomeric quadruplex ligands was synthesized and evaluated. The results from biophysical and biochemical assay indicated that introducing of positive charged aza-aromatic terminal group into the side chain of 9-position of berberine significantly improved the binding ability with G-quadruplex, and exhibited the inhibitory effect on the hybridization and on telomerase activity. These derivatives showed excellent selectivity for telomeric G-quadruplex DNA over duplex.
Superb-selective chemodosimetric signaling of sulfide in the absence and in the presence of CT-DNA and imaging in living cells by a plant alkaloid berberine analogue
Jana, Gopal Chandra,Khatun, Munira,Nayim, Sk,Das, Somnath,Maji, Anukul,Beg, Maidul,Patra, Anirudha,Bhattacharjee, Paromita,Bhadra, Kakali,Hossain, Maidul
, p. 2368 - 2380 (2019)
The present manuscript reports a lucrative design of a colorimetric and ratiometric chemodosimeter, 9-O-(2,4-dinitrobenzenesulfonyl)berberrubine (BER-S), with excellent water solubility for the superb selective detection of sulfides through a color alteration from yellow to red with a good limit of detection (LOD) of 56 nM in CP buffer solution (10 mM, pH 7.2). Interestingly, this work also includes a smart "turn-on" emission probe (BER-S/DNA complex) showing good linearity with an excellent LOD of 46 nM for recognizing sulfide anions. The probes, BER-S, and BER-S/DNA complex, displayed no interfering effect by other analytes or sulfur-containing inorganic compounds, like thiols. Characterization was carried out using IR, HRMS, and DFT for the BER-S probe, and time-resolved fluorescence lifetime measurement and fluorescence titration for the BER-S/DNA complex probe for elucidating their sensing mechanism. The detection of S2- in waste, tap, and drinking water by BER-S indicated its potential application in real sample analysis, while concentration variant cell imaging experiments (naked-eye red fluorescence) verified its cell-membrane permeability and capability for S2- imaging in living cells. This reaction-based sensing strategy in the presence of DNA may provide a potential platform for the design of a fluorescent chemodosimeter for extensive anion targets.
Synthesis, DNA-binding affinities, and binding mode of berberine dimers
Qin, Yong,Pang, Ji-Yan,Chen, Wen-Hua,Cai, Zongwei,Jiang, Zhi-Hong
, p. 25 - 32 (2006)
Six novel berberine dimers (3a-f) were synthesized in 37-84% yield from the reaction of berberrubine (2) with dihaloalkanes of varying lengths from two to seven carbons. Their interactions with calf thymus (CT) DNA and three double helical oligodeoxynucleotides, d(AAGAATTCTT)2, d(AAGCATGCTT) 2, and d(TAAGAATTCTTA)2, were investigated by means of fluorometric titration and ethidium bromide (EB) displacement experiments. Compared with the monomeric parent berberine (1), these dimers' DNA-binding affinities increased up to approximately 100-fold, suggesting a cooperative interaction of the two berberine subunits in the molecules. Furthermore, these dimers linked by different spacers show a prominent structure-activity relationship when bound with oligodeoxynucleotides. The relative binding affinities are in the order of 3b > 3a > 3c > 3d > 3e > 3f with d(AAGAATTCTT)2 and d(TAAGAATTCTTA)2, and 3b > 3c > 3a > 3d > 3e > 3f with d(AAGCATGCTT)2. Dimer 3b, linked with a propyl chain, exhibits the highest binding affinity. This suggests that a propyl chain may be the most suitable spacer to bridge the two berberine units for DNA binding. Spectrophotometric titration and competitive EB displacement of berberine (1) and dimer 3b indicate that both berberine and its dimers form intercalating complexes with duplex DNA. A larger redshift, a stronger hypochromic effect, and a much higher EB displacement ratio, observed in 3b, indicate that the dimer is in more intimate contact with DNA than berberine. In addition, no obvious binding of canadine (4), a hydrogenated product of berberine, with CT DNA was observed, suggesting critical roles of the quaternary ammonium cation and planar structure in the DNA-binding of berberine.
synthesis and evolution of berberine derivatives as a new class of antiviral agents against enterovirus 71 through the MEK/ERK pathway and autophagy
Wang, Yan-Xiang,Yang, Lu,Wang, Hui-Qiang,Zhao, Xiao-Qiang,Liu, Ting,Li, Ying-Hong,Zeng, Qing-Xuan,Li, Yu-Huan,Song, Dan-Qing
, (2018)
Taking berberine (BBR) as the lead, 23 new BBR derivatives were synthesized and examined for their antiviral activities against four different genotype enterovirus 71 (EV71) strains with a cytopathic effect (CPE) assay. Structure-activity relationship (SAR) studies indicated that introduction of a suitable substituent at the 9-position might be beneficial for potency. Among them, compound 2d exhibited most potent activities with IC50 values of 7.12-14.8 μM, similar to that of BBR. The effect of 2d was further confirmed in a dose-dependent manner both in RNA and protein level. The mechanism revealed that 2d could inhibit the activation of MEK/ERK signaling pathway. Meanwhile, it could suppress the EV71-induced autophagy by activating AKT and inhibiting the phosphorylation of JNK and PI3KIII proteins. We consider BBR derivatives to be a new family of anti-EV71 agents through targeting host components, with an advantage of broad-spectrum anti-EV71 potency.
Synthesis of linked berberine dimers and their remarkably enhanced DNA-binding affinities
Chen, Wen-Hua,Pang, Ji-Yan,Qin, Yong,Peng, Qian,Cai, Zongwei,Jiang, Zhi-Hong
, p. 2689 - 2692 (2005)
This communication describes the facile synthesis of five novel berberine dimers and their strong affinities toward double-stranded DNA. These berberine dimers were synthesized in 37-84% yields from the reaction of berberrubine with dihaloalkanes of varying lengths, and fully characterized by HRMS and 1H NMR. Compared with the monomeric parent berberine, these dimers showed greatly enhanced binding affinities up to approximately 100-fold, with two double helical oligodeoxynucleotides, d(AAGAATTCTT)2 and d(TAAGAATTCTTA)2, which was investigated by means of fluorescence spectrometry.
13-hydroxylation of tetrahydroberberine in cell suspension cultures of some Corydalis species
Iwasa,Kamigauchi
, p. 1511 - 1515 (1996)
Liquid chromatography/atmospheric pressure chemical ionization-mass spectrometry was applied to biotransformation experiments in cultured cells of Corydalis ophiocarpa as well as C. ochotensis var. raddeana. Hydroxylation at C-13 of tetrahydroberberine was shown to take place in cell cultures as well as in C. ophiocarpa plants. N-Methylation of tetrahydroberberine occurred to form the α-N-metho salt incorporating the B/C-cis-quinolizidine system. Introduction of the C-13 methyl with berberine as substrate was confirmed to provide 13-methylberberine. In addition, the reversible oxidation-reduction of the C ring of protoberberines was demonstrated. Copyright
Anti-Inflammation Associated Protective Mechanism of Berberine and its Derivatives on Attenuating Pentylenetetrazole-Induced Seizures in Zebrafish
Zhang, Baoyue,Wang, Lizhen,Ji, Xiuna,Zhang, Shanshan,Sik, Attila,Liu, Kechun,Jin, Meng
, p. 309 - 325 (2020)
Epileptic seizures are characterized by synchronized discharges of neurons, leading to the activation of inflammatory responses that in turn contributes to seizure progression. Berberine (BBR), a bioactive constituent extracted from berberis, has been known to relieve seizures in rodent models. In this study, we synthesized two derivatives of berberine (BBR-D1 and BBR-D2) to compare their seizure reducing effect with BBR in pentylenetetrazole (PTZ)-induced seizures in zebrafish. We found a structure-activity relationship between hydrophilic/hydrophobic composition of the derivatives and their anticonvulsant activity. We also investigated the underlying mechanism related to their anti-inflammatory effect during seizures. BBR and its derivatives increased the seizure onset latency and suppressed the seizure-like behavior after PTZ treatment. Zebrafish larvae pretreated with BBR and its derivatives showed recovery on c-fos expression and neuronal discharges during seizures. The inflammatory responses occurred during the progression of seizures, including the recruitment of macrophages and neutrophils as well as an up-regulation of tumor necrosis factor alpha (TNFα), interleukin 1 beta (il1β), and interleukin 6 (il6). This effect was significantly suppressed by the pretreatment of BBR and its derivatives. Our results suggest that BBR and its derivatives attenuate PTZ-induced seizures and modulate anti-inflammatory effect to potentially protect zebrafish from the occurrence of further seizures. From the tested compounds, BBR-D1 (the hydrophilic berberrubine) showed the strongest seizure reducing effect. [Figure not available: see fulltext.].
Berberine derivatives, preparation method thereof and application of berberine derivatives as p300 HAT small molecule inhibitor
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Paragraph 0048-0050; 0054-0055; 0066-0070, (2021/02/10)
The invention discloses berberine derivatives, a preparation method thereof and an application of the berberine derivatives as a p300 HAT small molecule inhibitor, and belongs to the technical field of medicinal chemistry. An effective component berberine hydrochloride in a natural product coptis chinensis is taken as a research object and is subjected to structural modification and transformationso as to obtain a series of berberine hydrochloride derivatives. The berberine derivatives have the characteristics of high activity, high selectivity and high safety for p300 HAT, and solves the problems of high cytotoxicity, weak affinity, low activity and poor selectivity of existing p300 HAT small molecule inhibitors.
Novel berberine derivative as well as synthesis method and application thereof
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Paragraph 0044-0046, (2021/01/29)
The invention discloses a novel berberine derivative as well as a synthesis method and application thereof, belongs to the field of imaging agents, and aims to derive the structure of isoquinoline alkaloid berberine, optimize derived sites on the basis of an early stage and introduce an F-containing side chain to prepare a series of probes with a myocardial targeting property. A 18F marker of theseries of compounds is successfully prepared through a marking experiment of positron nuclide 18F; the 18F-labeled novel berberine derivative is higher in myocardial uptake, raw materials are easy toobtain, the synthesis cost of a molecular probe is reduced, and clinical transformation is facilitated.
