Protoberberine Alkaloids Research Articles

Coptisine, a protoberberine alkaloid, relaxes mouse airway smooth muscle via blockade of VDLCCs and NSCCs.

Background/Aims: Recently, effective and purified ingredients of traditional Chinese medicine (TCM) were extracted to play crucial roles in the treatment of pulmonary diseases. Our previous research focused on TCM drug screening aimed at abnormal airway muscle contraction during respiratory diseases. Coptisine, an effective ingredient extracted from bitter herbs has shown a series of antioxidant, antibacterial, cardioprotective and neuroprotective pharmacological properties. In the current study, we questioned whether coptisine could also participate in asthma treatment through relaxing abnormal contracted mouse airway smooth muscle (ASM). The present study aimed to characterize the relaxant effects of coptisine on mouse ASM and uncover the underlying molecular mechanisms. Methods: To investigate the role of coptisine on pre-contracted mouse ASM, a series of biological techniques, including force measurement and patch-clamp experiments were employed. Results: Coptisine was found to inhibit high K+ or acetylcholine chloride (ACh)-induced pre-contracted mouse tracheal rings in a dose-dependent manner. Further research demonstrated that the coptisine-induced mouse ASM relaxation was mediated by alteration of calcium mobilization via voltage-dependent L-type Ca2+ channels (VDLCCs) and non-selective cation channels (NSCCs). Conclusion: Our data showed that mouse ASM could be relaxed by coptisine via altering the intracellular Ca2+ concentration through blocking VDLCCs and NSCCs, which suggested that this pharmacological active constituent might be classified as a potential new drug for the treatment of abnormal airway muscle contraction.

Optimization of the extraction and purification of Corydalis yanhusuo W.T. Wang based on the Q-marker uniform design method

Corydalis yanhusuo W.T. Wang alkaloids are mainly divided into three categories: protoberberine, prototropine and aporphine alkaloids. Therefore, we have taken into account these three alkaloid contents when extracting and purifying crude drugs, which is essential for the quality control of C. yanhusuo and its derivative products. Herein, we investigated the feasibility of the Q-marker uniform design method in the optimization of the extraction and purification of C. yanhusuo. In this study, Q-marker-based comprehensive scoring (CS) and uniform design methods were used to optimize the extraction and purification of C. yanhusuo. The inspective factors included the solvent concentration, pH, liquid–solid ratio, extraction time and frequency. Then 8 Q-markers, the total alkaloid extraction and the extraction rate were considered as the evaluating indicators during the process. The results indicated that the optimal reflux extraction process of C. yanhusuo was as follows: a total amount of 20 times 70% ethanol (pH = 10 of diluted ammonia), heating and refluxing twice, and extracting each time for 60 min. The results of nine-resin screening exhibited that NKA-9 macroporous adsorption resin had the best separation and purification effect on 8 kinds of C. yanhusuo alkaloids with stronger enrichment. During the optimal enrichment process and elution conditions, the water-soluble impurities were washed off with 5 BV distilled water at a volume flow rate of 2 BV/h, and the elution solvent was 70% ethanol with an elution volume flow rate of 1.5 BV/h and an elution dosage of 12 BV. Additionally, the total alkaloids of the obtained product were over 50%, of which eight quality markers were (+)-corydaline 3.55%, tetrahydropalmatine 3.13%, coptisine 2.79%, palmatine hydrochloride 2.24%, dehydrocorydaline 13.11%, (R)-(+)-corypalmine 2.37%, protopine 2.71% and glaucine 14.03%. Our data demonstrated that the optimal extraction and purification process was stable and feasible, which was expected to provide an experimental basis and reference for the industrial production of C. yanhusuo.

Natural protoberberine alkaloids, identified as potent selective LSD1 inhibitors, induce AML cell differentiation.

Natural protoberberine alkaloids were first identified and characterized as potent, selective and cellular active lysine specific demethylase 1 (LSD1) inhibitors. Due to our study, isoquinoline-based tetracyclic scaffold was identified as the key structural element for their anti-LSD1 activity, subtle changes of substituents attached to the core structure led to dramatic changes of the activity. Among these protoberberine alkaloids, epiberberine potently inhibited LSD1 (IC50=0.14±0.01μM) and was highly selective to LSD1 over MAO-A/B. Furthermore, epiberberine could induce the expression of CD86, CD11b and CD14 in THP-1 and HL-60 cells, confirming its cellular activity of inducing acute myeloid leukemia (AML) cells differentiation. Moreover, epiberberine prolonged the survival of THP-1 cells bearing mice and inhibited the growth of AML cells in vivo without obvious global toxicity. These findings give the potential application of epiberberine in AML treatment, and the isoquinoline-based tetracyclic scaffold could be used for further development of LSD1 inhibitors.

Isolation of Oxyberberine and β‐Sitosterol from Berberis lycium Royle Root Bark Extract and In Vitro Cytotoxicity against Liver and Lung Cancer Cell Lines

Berberis lycium Royle has been traditionally used to cure rheumatism, eye and ear diseases, malarial fever, diabetes, stomach disorders, and skin diseases. There is a least amount of data available on cytotoxic capacity of Berberis lycium from Pakistani origin, so on this basis, the present study was aimed to screen Berberis lycium root bark extracts for cytotoxicity against cancer cell lines and isolation of chemical constituents from the most cytotoxic extract. Initial screening of extracts was performed on HepG2 cells at 100 μg/mL for 72 hours of treatment by using an MTT assay. Active fractions were subjected to a series of column chromatographies for the isolation of cytotoxic compounds. Molecular structures were elucidated by using combined data from 1H-NMR, 13C-NMR, and ESI-MS graphs. Assessment of reduction in cell proliferation by isolated compounds was performed on three human cancer cell lines (SK-Hep-1, HepG2, and NCI-H1299). Both n-hexane and chloroform fractions were found active with percent cell viabilities of 8.41 ± 2.23 and 22.31 ± 9.11 in HepG2 cells compared with lupeol 35.43 ± 3.35 percent viability. A protoberberine alkaloid identified as oxyberberine was isolated from chloroform fraction while β-sitosterol was isolated from n-hexane fraction. Oxyberberine inhibited SK-Hep-1 cell proliferation under a dose-dependent manner with an IC50 value of 34.26 ± 3.34 μM while HepG2 cells showed 50% inhibition at 62.96 ± 4.12 μM. β-Sitosterol showed reduction in cell viability in SK-Hep-1 cells and HepG2 cells with IC50 values of 123.12 ± 3.51 μM and 140 ± 4.21 μM. This is the first report on the isolation of oxyberberine and β-sitosterol from Berberis lycium root bark and their cytotoxic evaluation against SK-Hep-1 and NCI-H1299 cells. The cytotoxic potential of Berberis lycium Royle extracts and isolated compounds is suggesting that it is a promising candidate for anticancer drug discovery.

Nuclear magnetic resonance based structure of the protoberberine alkaloid coralyne and its self-association by spectroscopy techniques

Coralyne is an important alkaloid due to its anti-cancer and other medicinal properties. It targets DNA in cells and acts as human topoisomerase-I poison, telomerase inhibitor and nucleic acid intercalator. It has high tendency to undergo self-association, which is a matter of concern for therapeutic applications. The understanding of its interaction with DNA requires precise knowledge of chemical shifts in Nuclear Magnetic Resonance (NMR) spectra besides self-association. The present study is the first report of a complete assignment of all 1H/13C resonances in NMR spectra of coralyne in DMSO-d6 using one dimensional 1H/13C and two dimensional NMR experiments. The chemical shift of all proton and several 13C resonances have also been obtained in D2O and ethanol-d6. The same has been calculated using Density Functional Theory (DFT). NMR spectra of coralyne show upfield shift of 0.6–1.2 ppm in aromatic ring protons suggesting stacking interactions. Apart from 11 intra molecular NOE cross peaks in 2D 1H–1H ROESY spectra, 3 short distance NOE correlations, H6–10OCH3, H5–10OCH3 and H12–16CH3, give direct independent evidence of the formation of a stacked dimer. The absorbance, fluorescence, circular dichroism and fluorescence lifetime experiments conducted in the present investigations corroborate results obtained by NMR.

Palmatine: A review of pharmacological properties and pharmacokinetics.

The aim of this review is to collect together the results of the numerous studies over the last two decades on the pharmacological properties of palmatine published in scientific databases like Scopus and PubMed, which are scattered across different publications. Palmatine, an isoquinoline alkaloid from the class of protoberberines, is a yellow compound present in the extracts from different representatives of Berberidaceae, Papaveraceae, Ranunculaceae, and Menispermaceae. It has been extensively used in traditional medicine of Asia in the treatment of jaundice, liver-related diseases, hypertension, inflammation, and dysentery. New findings describe its possible applications in the treatment of civilization diseases like central nervous system-related problems. This review intends to let this alkaloid come out from the shade of a more frequently described alkaloid: berberine. The toxicity, pharmacokinetics, and biological activities of this protoberberine alkaloid will be developed in this work.

Palmatine inhibits Zika virus infection by disrupting virus binding, entry, and stability

Zika virus (ZIKV) is an emerging vector-borne virus that is associated with severe congenital cerebral anomalies in fetuses and paralytic Guillain-Barré syndrome in adults. In the current global health crisis, there are no vaccines or therapeutics available for the treatment of ZIKV infection. In the present study, we evaluated the efficacy of the protoberberine alkaloid, palmatine, in inhibiting ZIKV and Japanese encephalitis virus (JEV). Palmatine was shown to bind to restricted viruses, inhibit ZIKV infection, and resist ZIKV-induced cytopathic effects. Palmatine was also shown to inhibit JEV infection in multiple cell lines. Overall, the effects of palmatine in disrupting ZIKV binding, entry, and stability indicate that this small molecule would be a good starting point for the development of treatments aimed at inhibiting ZIKV infection.

Jatrorrhizine inhibits mammary carcinoma cells by targeting TNIK mediated Wnt/β-catenin signalling and epithelial-mesenchymal transition (EMT)

BackgroundTraf2 and Nck interacting serine protein kinase (TNIK) is a tumour target protein which its high expression is closely related to the occurrence and development of mammary carcinoma cells. Molecular docking revealed that jatrorrhizine, a protoberberine alkaloid, exhibits good binding affinity and interaction with TNIK. However, the underlying mechanisms of jatrorrhizine targeting TNIK inhibits the proliferation and metastasis of breast cancer cells remain unclear. MethodsTo figure out the mechanisms in vitro and in vivo, the CRISPR/Cas9 technology was used to knockout TNIK gene and detected qualitatively by immunofluorescence and immunoblotting assay. The MTT cell viability assay for cytotoxicity test, the apoptosis were detected by flow cytometry, the migration and invasion were evaluated by colony formation, wound healing assay and cell invasion assay, respectively. Anticancer effects were further corroborated by 4T1/Luc homograft tumour model. ResultsThe results showed that targeted knockout of TNIK that attenuated Wnt/β-catenin signalling and epithelial-mesenchymal transition (EMT) expression, the effects were potentiated by the addition of jatrorrhizine. Moreover, jatrorrhizine distinctly inhibited the proliferation of MDA-MB-231, MCF-7 and 4T1 cells with IC50 values of 11.08 ± 1.19 μM, 17.11 ± 4.54 μM and 22.14 ± 2.87 μM, induced mitochondrial dysfunction and early apoptosis involving mitochondrial apoptotic pathway. These results were further corroborated by the 4T1 tumour-bearing mice, which showed that jatrorrhizine significantly suppressed the proliferation and metastasis of mammary carcinoma cells without obvious toxicity. ConclusionThese findings provide an overall perspective that jatrorrhizine potentially restrains TNIK regulating Wnt/β-catenin signalling and EMT expression for mammary cancer targeted therapy.

<p>Jatrorrhizine inhibits colorectal carcinoma proliferation and metastasis through Wnt/β-catenin signaling pathway and epithelial–mesenchymal transition</p>

PurposeJatrorrhizine (JAT) is a natural protoberberine alkaloid, possesses detoxification, bactericidal and hypoglycemic activities. However, its anti-cancer mechanism is not clear. This study aimed to investigate the mechanism of JAT through which inhibits colorectal cancer in HCT-116 and HT-29 cells.MethodsMTT assay and colony formation assay were used to check the cell proliferation ability. Cell apoptosis and cell cycle were measured by Hoechst 33342 staining and flow cytometry, respectively. Cell migration and invasion were detected by scratch wound healing assay and trans-well assay, respectively. Further, expression of related proteins was examined via Western blotting and the in vivo anti-cancer effect of JAT was confirmed by nude mice xenograft model.ResultsThe research showed that JAT inhibited the proliferation of HCT-116 and HT-29 cells with IC50 values of 6.75±0.29 μM and 5.29±0.13 μM, respectively, for 72 hrs. It has also showed a time dependently, cell cycle arrested in S phase, promoted cell apoptosis and suppressed cell migration and invasion. In addition, JAT inhibited Wnt signaling pathway by reducing β-catenin and increasing GSK-3β expressions. Increased expression of E-cadherin, while decreased N-cadherin, indicating that JAT treatment suppressed the process of cell epithelial–mesenchymal transition (EMT). In HCT-116 nude mice xenograft model, JAT inhibited tumor growth and metastasis, and induced apoptosis of tumor cells.ConclusionThis study demonstrated that JAT efficiently inhibited colorectal cancer cells growth and metastasis, which provides a new point for clinical treatment of colorectal cancer.

Quaternary protoberberine alkaloids and their interactions with DNA

The G-quadruplex DNA is commonly present in several protooncogenic-DNA promoters and participates in many important biological processes such as replication, transcription, and translation. Because of their supposed role in cancer, G-quadruplex DNA is often studied as a target for anti-cancer drugs. Quaternary protoberberine and tetrahydroprotoberberine alkaloids (corysamine, coptisine, stylopine), which are supposed to selectively bind these structures, have been compared in terms of stability with selected types of DNA. Influence of selected alkaloids on the stability of double-stranded DNA and non-canonical forms of DNA was observed by determining association constants of alkaloid–DNA complexes using spectroscopic methods—molecular absorption spectrometry, fluorescence spectrometry, and mass spectrometry. Furthermore, the effect of given alkaloids on the melting temperature of these DNA structures was determined using CD spectrometry. Competitive dialysis and electrospray mass spectrometry were performed for affinity comparison of certain alkaloids to different DNA structures including G-quadruplexes. These experiments have proven that corysamine and coptisine prefer interaction with G-quadruplexes in comparison to dsDNA and ssDNA, whereas tetrahydroprotoberberine alkaloid stylopine does not interact with any DNA whatsoever.

A new dimeric protoberberine alkaloid and other compounds from the tubers of Tinospora dentata

A new dimeric quaternary protoberberine alkaloid, bispalmatrubine (1), and thirteen known compounds (2-14) were purified from the tubers of Tinospora dentata. Their structures were determined by spectroscopic and spectrometric analytical methods. Among the isolates, eight compounds were examined for their in vitro anti-inflammatory potential and several tested alkaloids displayed moderate inhibitory effects of N-formyl-methionyl-leucyl-phenylalanine/cytochalasin B (fMLP/CB)-induced superoxide anion generation and elastase release.

Size-tunable Au@Ag nanoparticles for colorimetric and SERS dual-mode sensing of palmatine in traditional Chinese medicine

Palmatine is a protoberberine alkaloid separated from several plants and application as an anti-inflammatory and antibacterial agent in the therapy of gastrointestinal and genitourinary disorder. Thus, the fast quantification of palmatine is important in clinic medical assays. Herein, we report simple, fast and sensitive colorimetric visualization and surface-enhanced Raman spectroscopy (SERS) dual-mode detection of palmatine basing on bimetallic size tunable silver shell capped gold nanoparticles (Au@Ag NPs). Interesting, the best signals output for dual-mode sensing of palmatine were both 5 nm Ag shell thickness of Au@Ag NPs. Meanwhile, we found that the addition of NaHSO4 significantly improves the aggregating sensitivity of Au@Ag NPs to trace palmatine. Upon exposure to 0.1 μM level palmatine, NaHSO4-optimized Au@Ag NPs solution exhibits a highly sensitive color change from orange to green and rapid aggregation kinetics within the initial 5 min, which can directly be seen with the naked eye and monitored by UV–vis absorbance spectra. In addition, we measured palmatine by SERS with the excellent enhancement effect of Au@Ag NPs for further increase the sensitivity and selectivity. More importantly, other protoberberine alkaloids do not interfere with this dual-mode sensor due to the different interaction force between Au@Ag NPs and these alkaloids, and the applicability of the sensor is well demonstrated in real samples with satisfactory results. This provide a fast and simple assay for the rapid detection of palmatine in traditional Chinese medicine, the limit of detection (LOD) is 0.13 μM by the naked eye and 0.10 μM by UV–vis spectroscopy. Therefore, the size-tunable of NaHSO4-optimized Au@Ag NPs can be used not only as a naked-eye sensor of palmatine, but also as a highly selective SERS probe.

Ligand Selectivity in the Recognition of Protoberberine Alkaloids by Hybrid-2 Human Telomeric G-Quadruplex: Binding Free Energy Calculation, Fluorescence Binding, and NMR Experiments.

The human telomeric G-quadruplex (G4) is an attractive target for developing anticancer drugs. Natural products protoberberine alkaloids are known to bind human telomeric G4 and inhibit telomerase. Among several structurally similar protoberberine alkaloids, epiberberine (EPI) shows the greatest specificity in recognizing the human telomeric G4 over duplex DNA and other G4s. Recently, NMR study revealed that EPI recognizes specifically the hybrid-2 form human telomeric G4 by inducing large rearrangements in the 5′-flanking segment and loop regions to form a highly extensive four-layered binding pocket. Using the NMR structure of the EPI-human telomeric G4 complex, here we perform molecular dynamics free energy calculations to elucidate the ligand selectivity in the recognition of protoberberines by the human telomeric G4. The MM-PB(GB)SA (molecular mechanics-Poisson Boltzmann/Generalized Born) Surface Area) binding free energies calculated using the Amber force fields bsc0 and OL15 correlate well with the NMR titration and binding affinity measurements, with both calculations correctly identifying the EPI as the strongest binder to the hybrid-2 telomeric G4 wtTel26. The results demonstrated that accounting for the conformational flexibility of the DNA-ligand complexes is crucially important for explaining the ligand selectivity of the human telomeric G4. While the MD-simulated (molecular dynamics) structures of the G-quadruplex-alkaloid complexes help rationalize why the EPI-G4 interactions are optimal compared with the other protoberberines, structural deviations from the NMR structure near the binding site are observed in the MD simulations. We have also performed binding free energy calculation using the more rigorous double decoupling method (DDM); however, the results correlate less well with the experimental trend, likely due to the difficulty of adequately sampling the very large conformational reorganization in the G4 induced by the protoberberine binding.

A review on analytical methods for natural berberine alkaloids.

Berberine alkaloids, a group of protoberberine alkaloids under the classification of isoquinoline alkaloids, include berberine, coptisine, palmatine, columbamine, dehydrocorydaline, jatrorrhizine, and epiberberine from natural sources. Studies have shown that berberine alkaloids have various pharmacological functions, such as antibacterial, antiviral, blood pressure-lowering, hypoglycaemic, antiarrhythmia, and anticancer effects. Therefore, it is worthwhile to develop analytical methods to investigate the pharmacokinetics and activity mechanisms of berberine alkaloids and to study berberine alkaloids more comprehensively. Current analytical methods for berberine alkaloids include liquid chromatography, thin-layer chromatography, ultraviolet spectroscopy, capillary electrophoresis, and gas chromatography. The most widely used detection method is mass spectrometry. In order to provide a systematic and comprehensive summary and to serve as a reference for the future pharmacokinetics studies and analysis of berberine alkaloids, analytical methods for natural berberine alkaloids that have been used in the past ten years are reviewed here.

Palmatine Identified from Malaysian Local Plant Possess In vitro and In vivo Antidiabetic and Antioxidant Effect on High‐Fat Diet‐Induced Diabetic Rat Model

BackgroundCoscinium fenestratum (CF) (Gaertn.) Colebr is from the family Menispermaceae, is a woody plant found in Southeast Asia including Malaysia. Traditionally CF has been used for the treatment of many diseases including diabetes Mellitus. Our previous research identified Palmatine a protoberberine alkaloid to be the active bioactive compound present in CF.ObjectiveThe aim of this study was to investigate in vitro and in vivo anti‐diabetic, antioxidant Effect on High Fat Diet Induced Diabetic Rat Module.MethodThe ability of Palmatine to inhibit reactive oxygen specie (ROS) such as Lipid peroxidation, DPPH, Nitric oxide, Hydroxyl, free radical scavenging activity was evaluated. The in vitro antidiabetic activity of Palmatine was evaluated using alpha glycosidase, alpha amylase and Dipeptidyl peptidase IV enzyme. Sprague dawley rats weighing 180–200g was fed with high fat diet (HFD) for 60 days to induce diabetes. Rats with plasma glucose level of 11mmol/L or 200mg/dL and above after 60 days HFD feeding, were orally administered with Palmatine (2mg/kg) for 90 days. The plasma glucose level and body weight of the rats were measured weekly. After treatment, the rat blood was withdrawn via cardiac puncture for hematological studies. Liver and pancreas was harvested for antioxidant, histology, biochemical and lipid profile analysis.ResultPalmatine was able to inhibit free radicals generated by Nitric oxide, DPPH, Hydroxyl, and alpha glucosidase, and alpha amylase activities. Palmatine was able to reduce plasma glucose level, activate antioxidant enzymes such as superoxide dismutase, catalase, glutathione reductase and inhibit lipid peroxidation in HFD induced diabetic rats. Biochemical and hematological analysis showed a reduction of diabetic markers in rats such HbA1c, urea, alkaline phosphatase, aspartate transaminase, alanine aminotransferase, LDL‐cholesterol, Triglycerides, but increase HDL level.ConclusionPalmatine possess antidiabetic and antioxidant in HFD induced diabetic rat model and able to offer protection to kidney, liver and cardiovascular organs by reducing the disease markers (Diabetes Complication Prevention).Support or Funding InformationCentre of Excellence for Research, Value, Innovation and Entrepreneurship Research Grant Scheme UCSI University (UCSI‐CERVIE‐RGS Proj‐in‐FAS 039)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Evaluation of anti-onchocercal activity of pseudopalmatine, a quaternary protoberberine alkaloid of Enantia chlorantha (Syn. <i>Annickia chlorantha</i>)

As part of our efforts towards identifying and subsequently developing lead compounds from medicinal plants of Cameroon to combat neglected tropical diseases, we embarked to phytochemically investigate Enantia chlorantha (Syn. Annickia chlorantha). The rationale for choosing this plant is its numerous uses in folk medicine in Cameroon and other parts of Africa. In Cameroon the quaternary protoberberine alkaloids, columbamine (2), palmatine (3) and jatrorrizine (4) have been isolated from the stem back and combined to produce a phytomedicine (HEPAZOR®) used in the treatment of viral hepatitis. An alkaloidal extraction of the methanolic extract of the stem bark of the plant was carried-out and this afforded yellow amorphous solids whose structure was obtained using routine nuclear magnetic resonance spectroscopy (NMR), high pressure liquid chromatography coupled to an electrospray mass spectrometer (HPLC-ESI-MS) and comparison with literature. The compound was identified as pseudopalmatine (1), a quaternary protoberberine alkaloid. Preliminary screening of the compound on both adult and juvenile worms of Onchocerca ochengi, a close relative of Onchocerca volvulus, the parasite responsible for human onchocerciasis (river blindness), showed that compound (1) was inactive at a concentration of 500 μg/mL on the adult worms, but inhibited microfilariae motility completely at this same concentration and by 50 % at 250 μg/mL and was thus considered active. While this work to the best of our knowledge constitutes the first report on the anti-onchocercal activity of quaternary protoberberine alkaloids in general and pseudopalmatine (1) in particular isolated from E. Chlorantha, it has however opened a window for further investigation of the anti-onchoceral activity of this class of compounds. Key words: anti-onchocercal, pseudopalmatine, alkaloid, Enantia chlorantha

Anticancer and Reversing Multidrug Resistance Activities of Natural Isoquinoline Alkaloids and their Structure-activity Relationship.

The severe anticancer situation as well as the emergence of multidrug-resistant (MDR) cancer cells has created an urgent need for the development of novel anticancer drugs with different mechanisms of action. A large number of natural alkaloids, such as paclitaxel, vinblastine and camptothecin have already been successfully developed into chemotherapy agents. Following the success of these natural products, in this review, twenty-six types of isoquinoline alkaloids (a total of 379 alkaloids), including benzyltetrahydroisoquinoline, aporphine, oxoaporphine, isooxoaporphine, dimeric aporphine, bisbenzylisoquinoline, tetrahydroprotoberberine, protoberberine, protopine, dihydrobenzophenanthridine, benzophenanthridine, benzophenanthridine dimer, ipecac, simple isoquinoline, pavine, montanine, erythrina, chelidonine, tropoloisoquinoline, azafluoranthene, phthalideisoquinoline, naphthylisoquinoline, lycorine, crinane, narciclasine, and phenanthridone, were summarized based on their cytotoxic and MDR reversing activities against various cancer cells. Additionally, the structure-activity relationships of different types of isoquinoline alkaloid were also discussed. Interestingly, some aporphine, oxoaporphine, isooxoaporphine, bisbenzylisoquinoline, and protoberberine alkaloids display more potent anticancer activities or anti-MDR effects than positive control against the tested cancer cells and are regarded as attractive targets for discovery new anticancer drugs or lead compounds.

A Multi-Level Strategy Based on Metabolic and Molecular Genetic Approaches for the Characterization of Different Coptis Medicines Using HPLC-UV and RAD-seq Techniques.

Coptis plants (Ranunculaceae) to have played an important role in the prevention and treatment human diseases in Chinese history. In this study, a multi-level strategy based on metabolic and molecular genetic methods was performed for the characterization of four Coptis herbs (C. chinensis, C. deltoidea, C. omeiensis and C. teeta) using high performance liquid chromatography-ultraviolet (HPLC-UV) and restriction site-associated DNA sequencing (RAD-seq) techniques. Protoberberine alkaloids including berberine, palmatine, coptisine, epiberberine, columbamine, jatrorrhizine, magnoflorine and groenlandicine in rhizomes were identified and determined based on the HPLC-UV method. Among them, berberine was demonstrated as the most abundant compound in these plants. RAD-seq was applied to discover single nucleotide polymorphisms (SNPs) data. A total of 44,747,016 reads were generated and 2,443,407 SNPs were identified in regarding to four plants. Additionally, with respect to complicated metabolic and SNP data, multivariable statistical methods of principal component analysis (PCA) and hierarchical cluster analysis (HCA) were successively applied to interpret the structure characteristics. The metabolic variation and genetic relationship among different Coptis plants were successfully illustrated based on data visualization. Summarily, this comprehensive strategy has been proven as a reliable and effective approach to characterize Coptis plants, which can provide additional information for their quality assessment.

Jatrorrhizine Hydrochloride Suppresses RANKL-Induced Osteoclastogenesis and Protects against Wear Particle-Induced Osteolysis.

Wear particle-induced aseptic prosthetic loosening is a major complication associated with total joint arthroplasty (TJA). A growing body of evidence suggests that receptor activator of nuclear factor κ-B ligand (RANKL)-stimulated osteoclastogenesis and bone resorption are responsible for peri-implant loosening. Thus, agents which attenuate excessive osteoclast differentiation and function have been considered to offer therapeutic potential for prolonging the life of TJA implants. Jatrorrhizine hydrochloride (JH), a major protoberberine alkaloid isolated from the traditional Chinese herb Coptis chinensis, has been reported to have antimicrobial, antitumor, and antihypercholesterolemic and neuroprotective activities. However, its effects on osteoclast biology remain unknown. Here, we found that JH inhibited RANKL-induced osteoclast formation and bone resorption in vitro and exerted protection against titanium (Ti) particle-induced osteolysis in vivo. Biochemical analysis demonstrated that JH suppressed RANKL-induced activation of MAPKs (p38 and ERK) which down-regulated the production of NFATc1 and NFATc1-regulated osteoclastic marker genes, such as TRAP, CTR and CTSK. Collectively, our findings suggest that JH may be a promising anti-osteoclastogenesis agent for treating periprosthetic osteolysis or other osteoclast-related osteolytic diseases.

Gold Catalyzed Photoredox C1‐Alkynylation of N‐Alkyl‐1,2,3,4‐tetrahydroisoquinolines by 1‐Bromoalkynes with UVA LED Light

AbstractA synthetic method that combines [Au2(μ‐dppm)2]Cl2 (dppm=bis(diphenylphosphanyl)methane) and UVA LED (LED=light emitting diode) light (365 nm) to catalyze the regioselective C1‐alkynylation of N‐alkyl‐1,2,3,4‐tetrahydroisoquinolines (THIQs) with alkynyl bromides is described. The reaction mechanism was delineated to involve a reductive quench pathway to generate the two posited radical species of the nitrogen‐containing heterocycle and organic halide. In contrast, radical formation via an oxidative quench pathway was suggested to be operative in analogous control experiments with a 1‐iodoalkyne. The usefulness of this carbon‐carbon bond forming strategy was also exemplified by its application to the formal synthesis of the opioid analgesic drug methopholine and synthesis of a protoberberine alkaloid derivative.magnified image