Selective Sensing of Copper Ions by Mesoporous Porphyrinic Metal-Organic Framework Nanoovals.

Copper is a common element in the environment and human body. Exposure to high concentrations of Cu2+ potentially causes health issues, such as Wilson and Alzheimer's diseases. It is of great importance for the highly selective and sensitive detection of Cu2+. In this work, a porous metal-organic framework (MOF), PCN222, is employed for the selective and sensitive determination of Cu2+. The selectivity of PCN222 relies on the interaction between Cu2+ and the porphyrin core of PCN222. PCN222 stacked with porphyrin rings exhibits solvent adaptability, which overcomes the drawback of the natural porphyrinic enzyme (such as HRP). PCN222 is used for constructing a sensor which shows a linear range of Cu2+ concentration from 0.4 to 13 µmol L-1, and its limit of detection (LOD) is 50 nmol L-1. The response time is less than 3 s, which is faster than previous methods. This work opens up a new route to MOF applications in the detection of metal ions in complex environments.

Discovery of a highly potent orally bioavailable imidazo-[1, 2-a]pyrazine Aurora inhibitor.

Imidazo-[1, 2-a]pyrazine 1 is a potent inhibitor of Aurora A and B kinase in vitro and is effective in in vivo tumor models, but has poor oral bioavailbility and is unsuitable for oral dosing. We describe herein our effort to improve oral exposure in this class, resulting ultimately in the identification of a potent Aurora inhibitor 16, which exhibited good drug exposure levels across species upon oral dosing, and showed excellent in vivo efficacy in a mouse xenograft tumor model when dosed orally.

Rapid degradation of refractory organic pollutants by continuous ozonation in a micro-packed bed reactor.

Recently microreactor technology attracts attention due to the excellent multiphase mixing and enhanced mass transfer. Herein, a continuous ozonation system based on a micro-packed bed reactor (µPBR) was used to improve the dissolution rate of ozone and achieved a rapid and efficient degradation of refractory organic pollutants. The effects of liquid flow rate, gas flow rate, initial pH, initial O3 concentration and initial phenol concentration on the phenol and chemical oxygen demand (COD) removal efficiencies were also investigated. Experimental results showed that phenol and COD removal efficiencies under optimal conditions achieved 100.0% and 86.4%, respectively. Compared with large-scale reactors, the apparent reaction rate constant in µPBR increased by 1-2 orders of magnitude. In addition, some typical organic pollutants (including phenols, antibiotics and dyes) were treated by ozonation in µPBR. The removal efficiencies of these organic pollutants and COD achieved 100.0% and 70.2%-80.5% within 71 s, respectively. In this continuous treatment system, 100% of the unreacted ozone was converted to oxygen, which promoted the healthy development of aquatic ecosystems. Thus, this continuous system based on µPBR is a promising method in rapid and efficient treating refractory organic pollutants.

[Determination of new carmine in beverages by one step rapid solid phase extraction based on metal organic framework extractant].

New coccine is an azo pigment that is widely used in food. To mitigate potential health issues arising from excessive consumption, China has issued provisions on the allowed addition limit of new coccine in food. Currently, there are certain difficulties with establishing detection methods for such trace pigments in foods; for example, preprocessing is complex and time-intensive. In addition, the low content of the target substance in the sample could be disturbed by food matrix, resulting in poor detection sensitivity. Metal organic frameworks (MOFs), as a novel class of highly efficient adsorbents, have attracted increasing attention because of their stability and large specific surface area. MOFs are porous coordination crystal structures that connect metal clusters with organic ligands via coordination. Owing to their molecule-sized pores, MOFs can be used in various fields such as adsorption, catalysis, and drug dispersion. However, at the same time, their ultra-high specific surface area also leads to ultra-low weight of the material itself; this makes it difficult to collect the material even under high-speed centrifugation. In this study, a MOF material (PCN-222) with a high specific surface area was prepared by the coordination of the carboxyl group in the porphyrin ring and metal zirconium ions. To simplify pretreatment, the nanomaterials were filled into an injection solid phase extraction device for the rapid extraction of new coccine pigments from beverages. The morphology, structure, and properties of the PCN-222 nanomaterials were studied by transmission electron microscopy, particle size analysis, X-ray single-crystal diffraction, infrared spectroscopy, and ultraviolet spectroscopy. The specific surface area of the synthesized material was 979 m2/g. A high specific surface area was conducive to the adsorption of trace target compounds. The surface charge of the material could be controlled by adjusting the pH value of the solution, which was beneficial to the selective adsorption and desorption of ionic pigments. The π-π interaction between the benzene ring of the porphyrin ring and the benzene ring of the azo pigment also promoted extraction. Thus, the extractant exhibited strong enrichment performance for the new coccine anionic pigment. The solid phase extraction conditions were optimized, and it was found that saturated adsorption capacity was achieved by filling 3 mg of extractant. The effect of pH on adsorption was also explored; the adsorption effect was the best at pH 3. In the desorption experiment, N,N-dimethylformamide at pH 11 was conducive to better elution of the target. Further elution volume studies showed that maximum recovery could be achieved by adding 3 mL of eluent. Subsequently, the sample pretreatment time was reduced to 5 min. The enriched sample was separated using a Zorbax eclipse XDB-C18 column (250 mm×4.6 mm, 5 µm), eluted with an ammonium acetate-methanol solvent system, and detected at 254 nm. Under the optimum conditions, the recoveries of the samples at high, medium, and low levels reached 99.5%-109.4%, and the relative standard deviation was less than 3%. The limit of detection (LOD, S/N=3) of this method was 0.1 µg/L and the limit of quantification (LOQ, S/N=10) was 0.3 µg/L. In the actual sample detection experiment, the detection signal of new coccine in the sample was amplified by solid phase extraction to achieve enrichment. In addition, the extraction capacity of PCN-222 remained higher than 90% after four uses, and the synthesized material could be recycled. The high precision and low detection limit indicate that the method is suitable for the enrichment and detection of trace carmine in beverages. The findings of this study will aid in the development of a new solid phase extraction technology for food safety evaluation.

Hafnium oxide layer-enhanced single-walled carbon nanotube field-effect transistor-based sensing platform.

Single-walled carbon nanotube-based field effect transistors (SWCNT-FETs) are ideal candidates for fabricating sensors and have been widely used for chemical sensing applications. SWCNT-FETs have low selectivity because of the environmentally sensitive electronic properties of SWCNTs, and SWCNT-FETs also show a high noise signal and poor sensitivity because of charge trapping from Si-OH hydration of the SiO2/Si substrate on the SWCNTs. Herein, poly (4-vinylpyridine) (P4VP) was used for noncovalent attachment to SWCNTs and selective binding to copper ions (Cu2+). Importantly, the introduction of a hafnium-oxide (HfO2) layer through atomic layer deposition (ALD) overcame the charge trapping by SiO2 hydration and remarkably decreased the interference signal. The sensitivity of the P4VP/SWCNT/HfO2-FET sensor for Cu2+ was 7.9 µA µM-1, which was approximately 100 times higher than that of the P4VP/SWCNT/SiO2-FET sensor, and its limit of detection (LOD) was as low as 33 pmol L-1. Thus, the P4VP/SWCNT/HfO2-FET sensor is a promising candidate for the development of Cu2+-selective sensors and can be designed for the large-scale manufacturing of custom-made sensors in the future.

[Determination of carbendazim residues in Procambarus clarkii by high performance liquid chromatography-triple quadrupole mass spectrometry].

A novel method based on high performance liquid chromatography-triple quadrupole mass spectrometry (HPLC-MS/MS) was established for the determination of carbendazim in Procambarus clarkii. The sample was extracted by ethyl acetate under alkaline conditions and centrifuged. The supernatant was concentrated by rotary evaporation, redissolved, and then enriched and purified on a mixed-mode cation exchange solid phase extraction column (MCX). A C18 column was used with acetonitrile and water as mobile phases in a gradient elution. Ionization was performed using an electrospray positive ion source (ESI+), and detection was achieved by MS/MS in multiple reaction monitoring (MRM) mode. The linearity for carbendazim was good in the range of 0.5-50.0 µg/L; the linear equation was y=0.19988x+0.01842; and the correlation coefficient (r2) was 0.9985. The limit of detection (LOD) and limit of quantification (LOQ) were 0.25 µg/kg and 0.50 µg/kg, respectively. At spiked levels of 0.5, 1.0, 5.0, and 50.0 µg/kg, the recoveries ranged from 83.9% to 105.5%, and the relative standard deviation ranged from 1.1% to 3.2%. This method is simple and effective for the determination of carbendazim residues in P. clarkii.

Thiolated poly(aspartic acid)-functionalized two-dimensional MoS2, chitosan and bismuth film as a sensor platform for cadmium ion detection.

In this work, a sensitive electrochemical platform for determination of cadmium ions (Cd2+) is obtained using thiolated poly(aspartic acid) (TPA)-functionalized MoS2 as a sensor platform by differential pulse anodic stripping voltammetry (DPASV). The performance of the TPA-MoS2-modified sensor is systemically studied. It demonstrates that the TPA-MoS2 nanocomposite modified sensor exhibits superior analytical performance for Cd2+ over a linear range from 0.5 µg L-1 to 50 µg L-1, with a detection limit of 0.17 µg L-1. Chitosan is able to form a continuous coating film on the surface of the GC electrode. The good sensing performance of the TPA-MoS2-modified sensor may be attributed to the following factors: the large surface area of MoS2 (603 m2 g-1), and the abundant thiol groups of TPA. Thus, the TPA-MoS2-modified sensor proves to be a reliable and environmentally friendly tool for the effective monitoring of Cd2+ existing in aquacultural environments.

A new aptamer/black phosphorous interdigital electrode for malachite green detection.

Malachite Green (MG), a cationic triphenylmethane dye, has adverse effects on the immune and reproductive system. Thus, it is essential to develop a rapid, sensitive and high-selective method for determination of MG. Black phosphorus (BP) has high charge-carrier mobility (∼1000 cm2 V-1 s-1) and high adsorption capacity for cationic dyes (i.e. MG) through both electrostatic and hydrophobic interactions. Thus, it potentially plays as a high-sensitive sensing platform for detecting MG. However, BP degrades within 12 h under humid condition, which limits its applications. To overcome this issue, cysteine (CYS) is used for protecting BP from oxidation and ceasing its degradation. To the best of our knowledge, it is the first time that CYS is used to functionalize BP, and a silicon interdigital electrode is fabricated with the functionalized BP and aptamer. The BP-based interdigital electrode shows a lowest detection limit of 0.3 ng L-1 toward MG. This work provides a new route to prepare a large scale and selective biosensor for MG monitoring on site in future.

Passivation of black phosphorus as organic-phase enzyme platform for bisphenol A determination.

Black phosphorus (BP) has a high charge-carrier mobility (∼1000 cm2 V-1 s-1), but the bare BP degrades rapidly in the presence of oxygen and water which limits the application of the BP. In this study, a simple, non-covalent passivation strategy is developed by modifying of the BP with hexamethylendiamine (HA). The functionalized BP exhibits good stability over 4 weeks. The organic phase interdigital electrode which is constructed by stable HA/BP and tyrosinase displays lowest noise signal (0.025 nA) and relatively low detection limit (10 nmol L-1) for bisphenol A. This work provides a new strategy for construction of novel biofuel cell, bioelectronics and biosensors.

Piperazine-based CCR5 antagonists as HIV-1 inhibitors. IV. Discovery of 1-[(4,6-dimethyl-5-pyrimidinyl)carbonyl]- 4-[4-[2-methoxy-1(R)-4-(trifluoromethyl)phenyl]ethyl-3(S)-methyl-1-piperazinyl]- 4-methylpiperidine (Sch-417690/Sch-D), a potent, highly selective, and orally bioavailable CCR5 antagonist.

The nature and the size of the benzylic substituent are shown to be the key to controlling receptor selectivity (CCR5 vs M1, M2) and potency in the title compounds. Optimization of the lead benzylic methyl compound 3 led to the methoxymethyl analogue 30, which had excellent receptor selectivity and oral bioavailability in rats and monkeys. Compound 30 (Sch-417690/Sch-D), a potent inhibitor of HIV-1 entry into target cells, is currently in clinical trials.

SCH 1473759, a novel Aurora inhibitor, demonstrates enhanced anti-tumor activity in combination with taxanes and KSP inhibitors.

PURPOSE: Aurora kinases are required for orderly progression of cells through mitosis, and inhibition of these kinases by siRNA or small molecule inhibitors results in cell death. We previously reported the synthesis of SCH 1473759, a novel sub-nanomolar Aurora A/B inhibitor. METHODS: We utilized SCH 1473759 and a panel of tumor cell lines and xenograft models to gain knowledge about optimal dosing schedule and chemotherapeutic combinations for Aurora A/B inhibitors. RESULTS: SCH 1473759 was active against a large panel of tumor cell lines from different tissue origin and genetic backgrounds. Asynchronous cells required 24-h exposure to SCH 1473759 for maximal induction of >4 N DNA content and inhibition of cell growth. However, following taxane- or KSP inhibitor-induced mitotic arrest, less than 4-h exposure induced >4 N DNA content. This finding correlated with the ability of SCH 1473759 to accelerate exit from mitosis in response to taxane- and KSP inhibitor-induced arrest. We tested various dosing schedules in vivo and demonstrated SCH 1473759 dose- and schedule-dependent anti-tumor activity in four human tumor xenograft models. Further, the efficacy was enhanced in combination with taxanes and found to be most efficacious when SCH 1473759 was dosed 12-h post-taxane treatment. CONCLUSIONS: SCH 1473759 demonstrated potent mechanism-based activity, and activity was shown to be enhanced in combination with taxanes and KSP inhibitors. This information may be useful for optimizing the clinical efficacy of Aurora inhibitors.

Aurora kinase inhibitors based on the imidazo[1,2-a]pyrazine core: fluorine and deuterium incorporation improve oral absorption and exposure.

Aurora kinases are cell cycle regulated serine/threonine kinases that have been linked to cancer. Compound 1 was identified as a potent Aurora inhibitor but lacked oral bioavailability. Optimization of 1 led to the discovery of a series of fluoroamine and deuterated analogues, exemplified by compound 25, with an improved pharmacokinetic profile. We found that blocking oxidative metabolism at the benzylic position and decreasing the basicity of the amine are important to obtaining compounds with good biological profiles and oral bioavailability.

Discovery of a Potent, Injectable Inhibitor of Aurora Kinases Based on the Imidazo-[1,2-a]-Pyrazine Core.

The imidazo-[1,2-a]-pyrazine (1) is a dual inhibitor of Aurora kinases A and B with modest cell potency (IC50 = 250 nM) and low solubility (5 µM). Lead optimization guided by the binding mode led to the acyclic amino alcohol 12k (SCH 1473759), which is a picomolar inhibitor of Aurora kinases (TdF K d Aur A = 0.02 nM and Aur B = 0.03 nM) with improved cell potency (phos-HH3 inhibition IC50 = 25 nM) and intrinsic aqueous solubility (11.4 mM). It also demonstrated efficacy and target engagement in human tumor xenograft mouse models.

Discovery and characterization of vicriviroc (SCH 417690), a CCR5 antagonist with potent activity against human immunodeficiency virus type 1.

Inhibiting human immunodeficiency virus type 1 (HIV-1) infection by blocking the host cell coreceptors CCR5 and CXCR4 is an emerging strategy for antiretroviral therapy. Currently, several novel coreceptor inhibitors are being developed in the clinic, and early results have proven promising. In this report, we describe a novel CCR5 antagonist, vicriviroc (formerly SCH-D or SCH 417690), with improved antiviral activity and pharmacokinetic properties compared to those of SCH-C, a previously described CCR5 antagonist. Like SCH-C, vicriviroc binds specifically to the CCR5 receptor and prevents infection of target cells by CCR5-tropic HIV-1 isolates. In antiviral assays, vicriviroc showed potent, broad-spectrum activity against genetically diverse and drug-resistant HIV-1 isolates and was consistently more active than SCH-C in inhibiting viral replication. This compound demonstrated synergistic anti-HIV activity in combination with drugs from all other classes of approved antiretrovirals. Competition binding assays revealed that vicriviroc binds with higher affinity to CCR5 than SCH-C. Functional assays, including inhibition of calcium flux, guanosine 5'-[35S]triphosphate exchange, and chemotaxis, confirmed that vicriviroc acts as a receptor antagonist by inhibiting signaling of CCR5 by chemokines. Finally, vicriviroc demonstrated diminished affinity for the human ether a-go-go related gene transcript ion channel compared to SCH-C, suggesting a reduced potential for cardiac effects. Vicriviroc represents a promising new candidate for the treatment of HIV-1 infection.