15401-69-1Relevant academic research and scientific papers
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.
Deciphering the positional impact of chlorine in a new series of berberine analogues towards the superb-selective "turn-on" hydrophobic signaling of bovine serum albumin at physiological pH
Jana, Gopal Chandra,Nayim, Sk,Sahoo, Nandan Kumar,Das, Somnath,Aktara, Mt Nasima,Patra, Anirudha,Islam, Md. Maidul,Hossain, Maidul
, p. 1761 - 1771 (2020)
The optical signals of serum albumin (SA) provide precious information for realizing its native functions, in addition to developing related biomedical applications. Herein, we report a new class of easy synthesizable and water-soluble compounds (BZ1-BZ5) based on different chlorine positions on 9-O-benzyl-substituted berberine scaffolds for the selective detection of bovine serum albumin (BSA) in CP buffer solution (10 mM, pH 7.2) based on two competing factors: hydrophobic interactions and steric repulsion. The frail emission intensities of these probes were enhanced upon the addition of BSA; exceptionally, a remarkable increase in emission intensity (140-fold) and remarkable lifetime and quantum yield increases make BZ4 an excellent fluorescence turn-on hydrophobic BSA sensor. Selectivity and co-existence studies involving other proteins, free tryptophan, etc. revealed that the microenvironment around the tryptophan moiety in BSA incites drastic spectral changes upon the introduction of BSA. Moreover, the most efficient lumino-probe, BZ4, can detect bovine serum albumin at a nanomolar level (LOD = 3.3 nM) with a broadened range of linearity and slight altering of the secondary structure of the protein. Our experimental results and docking simulation studies show that the probe BZ4 binds preferentially at "binding site II" of BSA. In addition, the binding and conformational alterations of BSA provoked by these analogues have been intensely investigated, and we fruitfully relate the binding results to the sensing outcome. The obtained results reveal how the different positioning of chlorine in benzyl-substituted berberine affects the hydrophobic sensing of BSA, making these probes a new category of BSA selective material with potential applications in proteome research.
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.
Antibacterial activity and structure-activity relationships of berberine analogs
Iwasa,Kamigauchi,Ueki,Taniguchi
, p. 469 - 478 (1996)
Analogs of berberine 1 and related compounds were prepared to evaluate structure-activity relationships. Among the 13-alkyl-substituted and the 13- unsubstituted protoberberinium salts, the 13-ethyl-9-ethoxyl homolog 30, the 13-ethyl analog 29, and the 13-methyl derivative 3 showed an increase in antibacterial activity against Staphylococcus aureus by eight-, four- and twofold respectively over the parent base berberine 1; this is suggestive that steric effects play a significant role in the antibacterial activity. Reduction of the protoberberinium salts yielding the tetrahydro derivatives greatly reduced the antibacterial activity. Replacement of methoxyl groups at the C-2 and the C-3 of ring A by a methylcnedioxy group resulted in increased antibacterial activity. These data strongly suggest that the quaternary nitrogen atom such as in protoberberinium salts, an alkylsubstituent at C- 13, and a methylenedioxy function at C-2 and C-3 are required for enhanced activity. Tetrahydroprotoberberine α-N-metho salts showed higher activity than tetrahydroprotoberberine hydrochlorides, but appreciably lower activity than protoberberinium salts. The effects of substitution at C-13 and on ring A in the α-N-metho salt were similar to those in protoberberinium salts. Stereochemical changes of the B/C ring juncture from trans to cis, and of the methyl group at C-13 from α to β, had, respectively, marked and slight effects on the activity. The tested compounds were less active against Escherichia coli (Gram-negative bacterium) and Candida albicans (fungus) than S aureus (Gram-positive bacterium).
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 novel berberine derivatives with balanced cholinesterase and prolyl oligopeptidase inhibition profile
Sobolova, Katerina,Hrabinova, Martina,Hepnarova, Vendula,Kucera, Tomas,Kobrlova, Tereza,Benkova, Marketa,Janockova, Jana,Dolezal, Rafael,Prchal, Lukas,Benek, Ondrej,Mezeiova, Eva,Jun, Daniel,Soukup, Ondrej,Korabecny, Jan
, (2020)
Berberine, a naturally occurring compound, possesses an interesting multipotent pharmacological profile potentially applicable for Alzheimer's disease (AD) treatment. In this study, a series of novel 22 berberine derivatives was developed and tested in vitro. Berberine core was substituted at position 9-O of its aromatic ring region. All the hybrids under the study revealed multi-targeted profile inhibiting prolyl oligopeptidase, acetylcholinesterase and butyrylcholinesterase highlighting 4a, 4g, 4j, 4l and 4s possessing balanced activities in the micromolar range. The top-ranked candidates in terms of the most pronounced potency against POP, AChE and BChE can be classified as 4d, 4u and 4v, bearing 4-methylbenzyl, (naphthalen-2-yl)methylene and 1-phenoxyethyl moieties, respectively. In vitro data were corroborated by detailed kinetic analysis of the selected lead molecules. 4d, 4u and 4v were also inspected for their potential to inhibit aggregation of two abberant proteins in AD, namely amyloid beta and tau, indicating their potential disease-modifying properties. To explain the results of our study, we carried out docking simulation to the active sites of the respective enzyme with the best berberine derivatives, along with QSAR study. We also investigated compounds’ potential permeability through blood-brain barrier by applying parallel artificial membrane permeation assay and addressed their cytotoxicity profile.
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.
Synthesis, hypolipidemic and antifungal activity of tetrahydroberberrubine sulfonates
Nechepurenko,Shirokova,Khvostov,Frolova,Sinitsyna,Maksimov,Bredikhin,Komarova,Fadeev,Luzina,Tolstikova,Salakhutdinova
, p. 1052 - 1060 (2019)
The paper describes the synthesis of new tetrahydroberberrubine derivatives containing polyfl uorophenyl- or alkylsulfonate groups at the O(9) position as well as those containing or not containing a bromine atom at the C(12) position. In a model of acute Triton-induced hyperlipidemia, tetrahydroberberrubine 9-O-(heptafluoro-4’-toluene)sulfonate was shown to reduce the cholesterol level by 23.5%, which is comparable with the eff ect of Simvastatin. At a concentration of 32 μg mL?1, tetrahydroberberrubine 9-O-pentafluorobenzenesulfonate inhibits the growth of the fungus Cryptococcus neoformans by 81.3±3.5%.
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.
Two telomerase-targeting Pt(ii) complexes of jatrorrhizine and berberine derivatives induce apoptosis in human bladder tumor cells
Qin, Qi-Pin,Wang, Zhen-Feng,Huang, Xiao-Ling,Tan, Ming-Xiong,Luo, Zhi-Hui,Wang, Shu-Long,Zou, Bi-Qun,Liang, Hong
, p. 15247 - 15254 (2019)
Two novel Pt(ii) complexes, [Pt(B-TFA)Cl]Cl (Pt1) and [Pt(J-TFA)Cl]Cl (Pt2) with jatrorrhizine and berberine derivatives (B-TFA and J-TFA) were first prepared as desirable luminescent agents for cellular applications and potent telomerase inhibitors, which can induce bladder T-24 tumor cell apoptosis by targeting telomerase, together with induction of mitochondrial dysfunction, telomere DNA damage and cell-cycle arrest. Importantly, T-24 tumor inhibition rate (TIR) was 50.4% for Pt2, which was higher than that of Pt1 (26.4%) and cisplatin (37.1%). Taken together, all the results indicated that jatrorrhizine and berberine derivatives Pt1 and Pt2 show low toxicity and could be novel Pt-based anti-cancer drug candidates.
