Chemoenzymatic Synthesis of Sterically Hindered Biaryls by Suzuki Coupling and Vanadium Chloroperoxidase Catalyzed Halogenations.

Halogenated biaryls are vital structural skeletons in bioactive products. In this study, an effective chemoenzymatic halogenation by vanadium-dependent chloroperoxidase from Camponotus inaequalis (CiVCPO) enabled the transformation of freely rotating biaryl bonds to sterically hindered axis. The yields were up to 84 % for the tribrominated biaryl products and up to 65 % when isolated. Furthermore, a one-pot, two-step chemoenzymatic strategy by incorporating transition metal catalyzed Suzuki coupling and the chemoenzymatic halogenation in aqueous phase were described. This strategy demonstrates a simplified one-pot reaction sequence with organometallic and biocatalytic procedures under economical and environmentally beneficial conditions that may inspire further research on synthesis of sterically hindered biaryls.

Metabolomics study of polysaccharide extracts from Polygonatum sibiricum in mice based on 1 H NMR technology.

BACKGROUND: Polygonatum sibiricum Liliaceae perennial herb, as a commonly used medicine and food homologous plant, has been widely used in clinical practice of Chinese medicine since ancient times, with a history of 2000 years. As the main active ingredient, P. sibiricum polysaccharides have important pharmacological effects in blood sugar reduction and antitumor, antioxidant and liver protection. RESULTS: Mouse models of P. sibiricum polysaccharides were used in combination with 1 H NMR to investigate the metabolic regulation mechanism in mouse tissue and blood. The metabolite maps of the control group and the drug group in the liver had significant changes. The main differential metabolites were glucose 6-phosphate, inositol, lactose, glutamylglycine, galactose, rhamnose, cis-aconitic acid and histidine, indicating that there was definite correlation between the metabolic detection based on 1 H NMR and the metabolic characteristics of P. sibiricum. The common differential metabolites obtained by overall metabolism analysis were 3-hydroxybutyric acid, d-ribose, adenosine phosphate, inositol, fructose 6-phosphate, histidine, aspartic acid and cis-aconitic acid. CONCLUSIONS: This work forms the basis for identification of metabolic states combined with metabolic pathways, which could be used as diagnostic and prognostic indicators, providing therapeutic targets for new diseases. © 2020 Society of Chemical Industry.

Evaluation of the antioxidant and endothelial protective effects of Lysimachia christinae Hance (Jin Qian Cao) extract fractions.

BACKGROUND: Lysimachia christinae Hance is a traditional Chinese medicine with diuretic, detumescent, and detoxifying effects. Our aimed to optimize the extraction protocol to maximize the yield of flavonoids from Lysimachia christinae Hance, and evaluate the pharmacological activities of four fractions, namely, petroleum ether (PE), ethyl acetate (EA), n-butanol (NB), and aqueous (AQ) fractions, of the ethanolic extract of Lysimachia christinae Hance. METHODS: The flavonoid monomers in the crude extract were characterized via high performance liquid chromatography (HPLC), were used as markers for extract quality control and standardization. The total flavonoid, total phenolic, and total polysaccharide contents of each fraction were determined by spectrophotometry. Further, the in vitro free radical (diphenylpicrylhydrazyl, 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid), superoxide, and hydroxyl radicals) scavenging activities, and antioxidant capacity in endothelial cells were evaluated for each fraction. RESULTS: After optimizing the extraction protocol to maximize the total flavonoid yield from L. christinae Hance, the NB fractions had the highest total flavonoid (39.4 ± 4.55 mg RE/g), total phenolic (41.1 ± 3.07 mg GAE/g) and total polysaccharide (168.1 ± 7.07 mg GE/g); In addition, the NB fraction of the ethanolic extract of L. christinae Hance reveal the strongest radical-scavenging activity, antioxidant activity and protective effects against H2O2-induced injury in HUVECs. CONCLUSIONS: Among the four fractions of L. christinae Hance, the NB fraction showed the most potent antioxidant and endothelial protective effects, which may be attributed to its high flavonoid, phenolic contents and optimal portfolio of different active ingredients of NB fractions of the ethanolic extract of L. christinae Hance. This study might improve our understanding of the pharmacological activities of L. christinae Hance, thereby facilitating its use in disease prevention and treatment.

pH, redox and photothermal tri-responsive DNA/polyethylenimine conjugated gold nanorods as nanocarriers for specific intracellular co-release of doxorubicin and chemosensitizer pyronaridine to combat multidrug resistant cancer.

Pharmacotherapy of multidrug resistant (MDR) cancer remains a challenging task in clinic. Herein, a pH-responsive DNA and disulfide-linked polyethylenimine functionalized gold nanorod was developed for specific co-delivery of chemotherapeutic agent doxorubicin (DOX) and chemosensitizer pyronaridine (PND) to effectively overcome MDR cancer cells. DOX and PND were firstly carried by a multifunctional nanocomplex for reversing MDR cancer. The nanocomplex can responsively and rapidly release its drugs payload under acidic pH environment (pH, ~5), intracellular GSH concentration content (5 mM) and/or 808 nm NIR laser irradiation. Compared to free DOX, the nanocomplex displayed greatly increased cytotoxicity to MDR MCF-7/ADR cancer cells (IC50, 70.68:6.21 µg/mL). The application of NIR radiation further improved the DOX release and enhanced the antitumor effects of the namomedicine (IC50, drops to 2.88 µg/mL). Consequently, this new nanocomplex exerted greatly increased potency against the MDR cancer cells over free DOX (~20 fold).

One-pot synthesis of single-crystal Pt nanoplates uniformly deposited on reduced graphene oxide, and their high activity and stability on the electrocalalytic oxidation of methanol.

We demonstrate a one-pot thermoreduction approach towards the preparation of single-crystal Pt nanoplates, which were uniformly deposited on the reduced graphene oxide (RGO) using polyvinylpyrrolidone (PVP) as a stabilizer. The size of Pt nanoplates can be tuned from 6.8 to 10.1 nm by controlling Pt loading. The as-prepared Pt/PVP/RGO catalysts show high stability and activity towards the methanol oxidation reaction (MOR). Their MOR current can reach up to 401 mA mg(-1) Pt and MOR current can maintain 89.4% of its initial value after 10 000 potential cycles.

Association of smoking cessation patterns and untreated smoking with glaucoma, cataract, and macular degeneration: a population-based retrospective study.

This study aims to assess the association between nicotine replacement therapy (NRT), varenicline, and untreated smoking with the risk of developing eye disorders. We employed a new-user design to investigate the association between NRT use and the incidence of eye disorders by the Taiwan National Health Insurance program. This study included 8416 smokers who received NRT and 8416 smokers who did not receive NRT (control group) matched using propensity scores between 2007 and 2018. After adjustment for relevant factors, a multivariable Cox regression analysis revealed that compared with untreated smokers, NRT use was associated with a significantly reduced risk of macular degeneration (hazard ratio [HR]: 0.34; 95% confidence interval [CI]: 0.13-0.87, P = 0.024). When stratified by dose, short-term NRT use (8-28 defined daily doses) was associated with significantly lower risk of glaucoma (HR: 0.35; 95% CI: 0.16-0.80, P = 0.012) and a trend toward reduced risk of cataract (HR: 0.60; 95% CI: 0.36-1.01, P = 0.053) compared to no treatment. However, these associations were not observed with long-term NRT use. The results of this real-world observational study indicate that NRT use, particularly short-term use, was associated with a lower risk of certain eye disorders compared to no treatment for smoking cessation. Long-term NRT use did not demonstrate the same benefits. Thus, short-term NRT may be a beneficial treatment strategy for reducing the risk of eye disorders in smokers attempting to quit. However, further evidence is required to verify these findings and determine the optimal duration of NRT use.

Simultaneous Determination of Six Alkaloids in Rat Plasma by SPE-HPLC-MS/MS and Their Pharmacokinetics after Oral Administration of Radix aconiti Preparata Extract.

Simultaneous determination of the content of six alkaloids (aconitine, hypoaconitine, mesaconitine, benzoylaconine, benzoylhypaconine, and benzoylmesaconine) in rat plasma is enabled by HPLC-MS/MS combined with microsolid phase extraction (micro-SPE). To study its pharmacokinetics in rat plasma, the extracted plasma sample was passed through a C18 extraction column and eluted with acetonitrile. The six alkaloids in the Radix aconiti Preparata extract can be completely separated as peaks with good shape. The six components in the plasma sample showed a good linear relationship within their respective linear ranges (R 2 > 0.997). The analysis of the six alkaloids can be completed within 20 min. This method has high intraday and interday precision, and the room temperature stability and freeze-thaw stability are good. The matrix effect of the plasma samples is between 86.4 and 114%. The metabolism of the six Aconitum alkaloids in plasma is analyzed using a two-compartment model, which is characterized by fast absorption, slow elimination, and good linear fit, R 2 > 0.99. The peak time (T max) for aconitine, hypaconitine, and neoaconitine ranged from 29.95 to 42.07 min, while the peak time (T max) for benzoaconitine, benzohypaconitine, and benzoxinaconitine ranged from 42.88 to 73.08 min. With the increased dosage, the bioavailability of Aconitum alkaloids decreased gradually. The method for the determination of Aconitum alkaloids in rat plasma by high performance liquid chromatography-tandem mass spectrometry is sensitive and accurate, which is suitable for rat plasma analysis. The results provide a scientific basis for metabolic study of Aconitum alkaloids in vivo, and pave the way for clinical use of Aconitum medicinal materials and extracts.

Citric acid coated ultrasmall superparamagnetic iron oxide nanoparticles conjugated with lactoferrin for targeted negative MR imaging of glioma.

The proposed study was to develop the preparation of ultrasmall superparamagnetic iron oxide nanoparticles (USPIONs) modified with citric acid, with surface conjugated with lactoferrin (Lf), which used as a potential targeted contrast agent for magnetic resonance imaging (MRI) of brain glioma. USPIONs were prepared by the thermal decomposition method. The hydrophobic USPIONs were coated with citric acid by the ligand exchange method. Then, Lf was conjugated into the surface of USPIONs. The obtained Lf-USPIONs were analyzed by fourier transform infrared (FTIR) spectroscopy and polyacrylamide gel electrophoresis. The size, size distribution, shape and superparamagnetic property of Lf-USPIONs were investigated with TEM and vibrating sample magnetometer (VSM). Both FTIR and electrophoresis analysis demonstrated the successful conjugation of Lf to the surface of USPIONs. The average size of Lf-USPIONs was about 8.4 ± 0.5 nm, which was determined using the statistics of measured over 100 nanoparticles in the TEM image, with a negative charge of -7.3 ± 0.2 mV. TEM imaging revealed that Lf-USPIONs were good in dispersion and polygonal in morphology. VSM results indicated that Lf-USPIONs were superparamagnetic and the saturated magnetic intensity was about 69.8 emu/g. The Lf-USPIONs also showed good biocompatibility in hemolysis, cytotoxicity, cell migration and blood biochemistry studies. MR imaging results in vitro and in vivo indicated that Lf-USPIONs exhibited good negative contrast enhancement. Taken together, Lf-USPIONs hold great potential for brain gliomas MR imaging as a nanosized targeted contrast agent.

Exploring the PROTAC degron candidates: OBHSA with different side chains as novel selective estrogen receptor degraders (SERDs).

As the mutant estrogen receptor (ER) continues to be characterized, breast cancer is becoming increasingly difficult to cure when treated with hormone therapy. In this regard, a strategy to selectively and effectively degrade the ER might be an effective alternative to endocrine therapy for breast cancer. In a previous study, we identified a novel series of 7-oxabicyclo[2.2.1]heptene sulfonamide (OBHSA) compounds as full ER antagonists while lacking the prototypical ligand side chain that has been widely used to induce antagonism of ERα. Further crystal structure studies and phenotypic assays revealed that these compounds are selective estrogen receptor degraders (SERDs) with a new mechanism of action. However, from a drug discovery point of view, there still is room to improve the potency of these OBHSA compounds. In this study, we have developed new classes of SERDs that contain the OBHSA core structure and different side chains, e.g., basic side chains, long alkyl acid side chains, and glycerol ether side chains, to simply mimic the degrons of proteolysis targeting chimera (PROTAC) and then investigated the structure-activity relationships of these PROTAC-like hybrid compounds. These novel SERDs could effectively inhibit MCF-7 cell proliferation and demonstrated good ERα degradation efficacy. Among the SERDs, compounds 17d, 17e and 17g containing a basic side chain with a N-trifluoroethyl substituent and a para methoxyl group at the phenyl group of the sulfonamide turned out to be the best candidates for ER degraders. A further docking study of these compounds with ERα elucidates their structure-activity relationships, which provides guidance to design new PROTAC degrons targeting ER for breast cancer therapy. Lastly, easy modification of these PROTAC-like SERDs enables further fine-tuning of their pharmacokinetic properties, including oral availability.

Insight on the changes of cassava and potato starch granules during gelatinization.

Gelatinization is an important property of starch for biomedical applications. However, studies on the changes in starch granules in terms of morphology, swelling, amylose leaching and so on during gelatinization, which are key to uncovering the starch gelatinization process, have rarely been reported. Herein, changes of cassava and potato starch granules during gelatinization were investigated. It was found that there is a substantial difference in the granule changes during gelatinization between cassava and potato starch. Cassava starch granules remain intact with slight swelling, with approximately 8.5% amylose leaching in water for 30 min at 60 °C. In sharp contrast, potato starch granules swell very well and rapidly, losing much integrity with 51.05% amylose leaching. The gelatinization time and temperature have much greater effects on the changes of potato starch granules than cassava starch granules.

Near-infrared triggered co-delivery of doxorubicin and quercetin by using gold nanocages with tetradecanol to maximize anti-tumor effects on MCF-7/ADR cells.

Previously, combination chemotherapy of doxorubicin (DOX) and quercetin (QUR) was developed to improve antitumor effects and reverse multidrug resistance and several biocompatible nanocarriers, such as liposomes and micelles, were validated for their targeted delivery. In this study, we report a near-infrared (NIR)-responsive drug delivery system based on DOX and QUR co-loaded gold nanocages (AuNCs) with biotin modification. The system was simply fabricated by filling the hollow interiors of AuNCs with tetradecanol (TD), a phase-change material with a melting point of 39°C, to control the drug release. The main cause of multidrug resistance (MDR) of DOX is the overexpression of P-glycoprotein (P-gp), which can be inhibited by QUR. Thus the combination chemotherapy of DOX and QUR may provide a promising strategy for MDR. The in vitro cytotoxicity of DOX and QUR at several fixed mass ratios was carried out and showed that the combination index (CI) was the smallest at the ratio of 1:0.2, indicating that the best synergistic effect was achieved. The resultant nanocomplex (abbreviated as BPQD-AuNCs) exhibited fast release (80% released in 20min) and strong cytotoxicity against MCF-7/ADR cells (IC50, 1.5µg/mL) under NIR irradiation. Additionally, BPQD-AuNCs were found to generate a large amount of reactive oxygen species (ROS), to inhibit P-gp expression and ATP activity. Taken together, the results show that BPQD-AuNC is a prospective nano-delivery system for overcoming multidrug-resistant cancer.

[Synthesis and vascular relaxing activity of arecoline derivatives coupled with nitric oxide donors].

AIM: To search for potential anti-atherosclerosis drugs with vascular relaxation activity, a series of agonists of endothelial targets were designed and synthesized. METHODS: Coupling N-methyl-1,2, 3,6-tetrahydrapyridine ring system with 3,4-dibenzenesulfonyl-1,2,5-oxadiazole-2-oxide through esterification or amidation, a series of arecoline derivatives containing NO donors were designed and synthesised. RESULTS: A novel series of compounds structurally related to arecoline have been prepared, the proposed structures of eighteen new compounds were established by IR, 1H NMR, MS spectroscopy and elemental analysis. The effects of the target compounds on the vasodilation activity were tested in the isolated preparation of mice thoratic aorta. CONCLUSION: This preliminary pharmacological tests showed that the candidates have good vasodilation activities and were worthy to be intensively studied.

[Synthesis and antibacterial activity of 3-(5-substituted phenyl-[1,3,4] oxadiazole-2-yl-methylenethio)-5-pyridin-3-yl-[1,2,4] triazole-4-yl-amines].

AIM: To study on synthesis and antibacterial activity evaluation of polyheterocycles. METHODS: The condensation of 4-amino-3-pyridin-3-yl-4H-[1,2,4] triazole-5-thiol with 2-chloromethyl-5-substituted phenyl-[1,3,4] oxadiazoles gave the corresponding title heterocycle amines, and the in vitro antibacterial activity was primarily evaluated by the method of cup-plate diffusion solution. RESULTS: Twelve novel compounds were synthesized, and their structures were confirmed by IR, 1H NMR, MS and element analysis. Biological screening results demonstrated that most of the compounds prepared showed good antibacterial activity. CONCLUSION: Oxadiazoles incorporting pyridyl triazole ring may be a pharmacophor structure in the molecule for developing antibacterial candidate drugs.

[Synthesis and antibacterial activity of 2-(3-pyridyl)-5-([(5-aryl-1,3,4-oxadiazol-2-yl) methylene]thio)-1,3,4-oxadiazoles].

AIM: Studies on synthesis and antibacterial activity of new heterocycles. METHODS: The cyclocondensation of [(3-pyridyl)-1,3,4-oxadiazol-2-yl] thio acetic acid with various aroyl hydrazines in the presence of POCl3 and xylene gave the corresponding titled compounds, and the in vitro antibacterial activity was primarily evaluated by the method of cupplate diffusion solution. RESULTS: Sixteen novel titled compounds were synthesized, their structures were confirmed by IR, 1HNMR, MS and elemental analysis. Biological screening results demonstrated that most of the compounds prepared displayed potential antibacterial activity. CONCLUSION: Oxadiazoles incorporting pyridyl oxadiazole ring may be usefully antibacterial candidate drugs.

Preparation and in vitro evaluation of novel poly(anhydride-ester)-based amphiphilic copolymer curcumin-loaded micelles.

Novel poly(anhydride-ester)-b-poly(ethylene glycol) copolymers (PAE-b-PEGs) were synthesized by esterization of methyl poly(ethylene glycol) and poly(anhydride-ester), which were obtained by the melt polycondensation of alpha,omega-acetic anhydride-terminated poly(L-lactic acid), and characterized by 1H-NMR and gel permeation chromatography. The two poly(anhydride-ester)-b-poly(ethylene glycols) (denoted as PAE-b-PEG2k and PAE-b-PEG5k) thus obtained can self-assemble in water to form micelles with hydrodynamic diameters of 92.5 and 97.5 nm above their critical micelle concentrations of 3.78 and 2.36 microg/mL, respectively. The curcumin-loaded PAE-b-PEG2k and PAE-b-PEG5k micelles were prepared by the solid dispersion method, and they could encapsulate approximately 7% (w/w) curcumin. The diameters of the micelles were stable for 5 days. Curcumin is released faster from the micelles at pH 5.0 than at pH 7.4. Curcumin is released from the micelles at a fast rate during the initial 12 h, followed by a zero-order release during the subsequent 200 h, both at pH 5.0 and 7.4. The IC50 values of the curcumin-loaded PAE-b-PEG2k and PAE-b-PEG5k micelles against HeLa cells are 12.41 and 15.31 microg/mL, respectively, which is lower than that of free curcumin (25.90 microg/mL). The PAE-b-PEG2k micelles are taken up faster than the PAE-b-PEG5k micelles by HeLa cells. Curcumin-loaded micelles can induce G2/M phase cell cycle arrest and apoptosis of HeLa cells.

Novel 4-arm poly(ethylene glycol)-block-poly(anhydride-esters) amphiphilic copolymer micelles loading curcumin: preparation, characterization, and in vitro evaluation.

A novel 4-arm poly(ethylene glycol)-block-poly(anhydride-esters) amphiphilic copolymer (4-arm PEG-b-PAE) was synthesized by esterization of 4-arm poly(ethylene glycol) and poly(anhydride-esters) which was obtained by melt polycondensation of α -, ω -acetic anhydride terminated poly(L-lactic acid). The obtained 4-arm PEG-b-PAE was characterized by (1)H-NMR and gel permeation chromatography. The critical micelle concentration of 4-arm PEG-b-PAE was 2.38 µg/mL. The curcumin-loaded 4-arm PEG-b-PAE micelles were prepared by a solid dispersion method and the drug loading content and encapsulation efficiency of the micelles were 7.0% and 85.2%, respectively. The curcumin-loaded micelles were spherical with a hydrodynamic diameter of 151.9 nm. Curcumin was encapsulated within 4-arm PEG-b-PAE micelles amorphously and released from the micelles, faster in pH 5.0 than pH 7.4, presenting one biphasic drug release pattern with rapid release at the initial stage and slow release later. The hemolysis rate of the curcumin-loaded 4-arm PEG-b-PAE micelles was 3.18%, which was below 5%. The IC50 value of the curcumin-loaded micelles against Hela cells was 10.21 µg/mL, lower than the one of free curcumin (25.90 µg/mL). The cellular uptake of the curcumin-loaded micelles in Hela cell increased in a time-dependent manner. The curcumin-loaded micelles could induce G2/M phase cell cycle arrest and apoptosis of Hela cells.

Recent progress in studying curcumin and its nano-preparations for cancer therapy.

A hydrophobic polyphenol compound extracted from turmeric, curcumin has been widely utilized as traditional medicines for centuries in China and India. Over the last decades, because of its low toxicity, extensive studies have been focused on its physicochemical properties and pharmacological activities on various diseases, such as cancer, cardio-vascular disease, inflammatory bowel, wound healing, Alzheimer's disease, rheumatoid arthritis, and diabetes. In particular, bioactivities of curcumin as an effective chemopreventive agent, chemo-/radio-sensitizer for tumor cells, and chemo-/radio-protector for normal organs, are of extraordinary research interests in the literature. Despite these advantages, applications of curcumin are limited in clinical trials because of its poor water solubility and low oral bioavailability. Nano-preparations as an emerging platform for the efficient delivery of anti-cancer drugs should overcome these problems. In this review, we at first briefly revisit important properties of curcumin as well as its uses in cancer treatments, and then overview various nano-preparations of curcumin for cancer therapy, including nanoparticles, liposomes, micelles, nanoemulsions, cyclodextrin complexes, nanodisks, nanofibres, solid lipid nanoparticles, and curcumin conjugates.