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.

Organic molecular passivation of phosphorene: An aptamer-based biosensing platform.

Black phosphorus (BP), also known as phosphorene (PP), is a fascinating two-dimensional (2D) material with extraordinary anisotropic mechanical, electronic and optoelectronic properties. However, PP is sensitive to oxygen and moisture and is completely degenerated by oxygen and humid air within 12 h, which limits its applications. Here, we coat PP with hexamethylenediamine (HMA), which allows the coated PP to maintain its original form in aqueous solution for over one month. The stable PP is dotted with gold nanoparticles to facilitate binding to a 3,3'4,4'-polychlorinated biphenyl (PCB77) aptamer (ap) as a biosensor. The aptamer biosensor based on gold nanoparticle-dotted PP nanocomposites (PP-AuNPs) exhibits superior analytical performance, and its sensitivity (391.1 µA cm-2) is approximately three times higher than that of an AuNP-based sensor (AuNP-Ap/Au electrode, 147.2 µA cm-2). This biosensor has a low detection limit (DL) of 33 pg L-1 toward PCB77 with a dynamic response range toward PCB77 from 100 pg L-1 to 10 µg L-1. This research opens up avenues for the use of PP to make multiplexed diagnosis platforms in aqueous systems.

A systematic exploration of the effects of flexibility and basicity on sigma (σ) receptor binding in a series of substituted diamines.

The sigma-1 receptor (S1R) has attracted a great deal of attention as a prospective drug target due to its involvement in numerous neurological disorders and, more recently, for its therapeutic potential in neuropathic pain. As there was no crystal structure of this membrane-bound protein reported until 2016, ligand generation was driven by pharmacophore refinements to the general model suggested by Glennon and co-workers. The generalised S1R pharmacophore comprises a central region where a basic amino group is preferred, flanked by two hydrophobic groups. Guided by this pharmacophore, S1R ligands containing piperazines, piperazinones, and ethylenediamines have been developed. In the current work, we systematically deconstructed the piperazine core of a prototypic piperazine S1R ligand (vide infra) developed in our laboratories. Although we did not improve the affinity at the S1R compared to the lead, we identified several features important for affinity and selectivity. These included at least one basic nitrogen atom, conformational flexibility and, for S1R, a secondary or tertiary amine group proximal to the anisole. Furthermore, S2R selectivity can be tailored with functional group modifications of the N-atom proximal to the anisole.

Simultaneous Preconcentration of Copper and Cadmium by Dispersive Liquid-Liquid Microextraction Using N,N'-Bis (2-Hydroxy-5-Bromo-Benzyl)1,2 Diaminopropane and Their Determination by Flame Atomic Absorption Spectrometry.

In the present study, the simultaneous preconcentration of copper and cadmium based on dispersive liquid-liquid microextraction as a prior step to their determination using flame atomic absorption spectrometry was developed. Carbon tetrachloride and N,N'-bis(2-hydroxy-5-bromo-benzyl)1,2 diaminopropane were used as the extraction solvent and chelating ligand, respectively. Some parameters that influence the extraction efficiency-e.g., sample pH, volume of extraction solvent (carbon tetrachloride), concentration of the chelating ligand, effect of salt addition, and sample volume-were investigated and optimized. With a preconcentration factor of 10, the LODs (3σ) for Cd and Cu were 0.69 and 1.98 µg/L, respectively. The accuracy of the developed method was evaluated by analyzing SLRS-5 river water and SRM 1573a tomato leaves certified reference materials. Results obtained were in good agreement with the certified values. The proposed method was successfully applied to river water, seawater, and black tea samples. Good spike recoveries, varying within the range of 97.5 to 116.9%, confirmed the good performance of the method in real sample analysis.

An upconversion nanoplatform for simultaneous photodynamic therapy and Pt chemotherapy to combat cisplatin resistance.

Platinum-based antineoplastic drugs are among the first-line chemotherapeutic agents against a variety of solid tumors, but toxic side-effects and drug resistance issues limit their clinical optimization. Novel strategies and platforms to conquer cisplatin resistance are highly desired. Herein, we assembled a multimodal nanoplatform utilizing 808 nm-excited and biocompatible core-shell-shell upconversion nanoparticles (UCNPs) [NaGdF4:Yb/Nd@NaGdF4:Yb/Er@NaGdF4] that were covalently loaded with not only photosensitizers (PSs), but also Pt(iv) prodrugs, which were rose bengal (RB) and c,c,t-[Pt(NH3)2Cl2(OCOCH2CH2NH2)2], respectively. The UCNPs had the capability to convert near infrared (NIR) light to visible light, which was further utilized by RB to generate singlet oxygen. At the same time, the nanoplatform delivered the Pt(iv) prodrug into cancer cells. Thus, this upconversion nanoplatform was able to carry out combined and simultaneous photodynamic therapy (PDT) and Pt chemotherapy. The nanoplatform was well characterized and the energy transfer efficiency was confirmed. Compared with free cisplatin or UCNPs loaded with RB only, our nanoplatform showed significantly improved cytotoxicity upon 808 nm irradiation in both cisplatin-sensitive and -resistant human ovarian cancer cells. A mechanistic study showed that the nanoparticles efficiently delivered the Pt(iv) prodrug into cancer cells, resulting in Pt-DNA damage, and that the nanoplatform generated cellular singlet oxygen to kill cancer cells. We, therefore, provide a comprehensive strategy to use UCNPs for combined Pt chemotherapy and PDT against cisplatin resistance, and our nanoplatform can also be used as a theranostic tool due to its NIR bioimaging capacity.

The zinc spark is an inorganic signature of human egg activation.

Egg activation refers to events required for transition of a gamete into an embryo, including establishment of the polyspermy block, completion of meiosis, entry into mitosis, selective recruitment and degradation of maternal mRNA, and pronuclear development. Here we show that zinc fluxes accompany human egg activation. We monitored calcium and zinc dynamics in individual human eggs using selective fluorophores following activation with calcium-ionomycin, ionomycin, or hPLCζ cRNA microinjection. These egg activation methods, as expected, induced rises in intracellular calcium levels and also triggered the coordinated release of zinc into the extracellular space in a prominent "zinc spark." The ability of the gamete to mount a zinc spark response was meiotic-stage dependent. Moreover, chelation of intracellular zinc alone was sufficient to induce cell cycle resumption and transition of a meiotic cell into a mitotic one. Together, these results demonstrate critical functions for zinc dynamics and establish the zinc spark as an extracellular marker of early human development.

Antibacterial Diamines Targeting Bacterial Membranes.

Antibiotic resistance is a growing threat to human health exacerbated by a lack of new antibiotics. We now describe a series of substituted diamines that produce rapid bactericidal activity against both Gram-positive and Gram-negative bacteria, including methicillin-resistant Staphylococcus aureus and stationary-phase bacteria. These compounds reduce biofilm formation and promote biofilm dispersal in Pseudomonas aeruginosa. The most potent analogue, 3 (1,13-bis{[(2,2-diphenyl)-1-ethyl]thioureido}-4,10-diazatridecane), primarily acts by depolarization of the cytoplasmic membrane and permeabilization of the bacterial outer membrane. Transmission electron microscopy confirmed that 3 disrupts membrane integrity rapidly. Compound 3 is also synergistic with kanamycin, demonstrated by the checkerboard method and by time-kill kinetic experiments. In human cell toxicity assays, 3 showed limited adverse effects against the HEK293T human kidney embryonic cells and A549 human adenocarcinoma cells. In addition, 3 produced no adverse effects on Caenorhabditis elegans development, survival, and reproduction. Collectively, diamines related to 3 represent a new class of broad-spectrum antibacterials against drug-resistant pathogens.

Covalent IR820-PEG-diamine nanoconjugates for theranostic applications in cancer.

Near-infrared dyes can be used as theranostic agents in cancer management, based on their optical imaging and localized hyperthermia capabilities. However, their clinical translatability is limited by issues such as photobleaching, short circulation times, and nonspecific biodistribution. Nanoconjugate formulations of cyanine dyes, such as IR820, may be able to overcome some of these limitations. We covalently conjugated IR820 with 6 kDa polyethylene glycol (PEG)-diamine to create a nanoconjugate (IRPDcov) with potential for in vivo applications. The conjugation process resulted in nearly spherical, uniformly distributed nanoparticles of approximately 150 nm diameter and zeta potential -0.4±0.3 mV. The IRPDcov formulation retained the ability to fluoresce and to cause hyperthermia-mediated cell-growth inhibition, with enhanced internalization and significantly enhanced cytotoxic hyperthermia effects in cancer cells compared with free dye. Additionally, IRPDcov demonstrated a significantly longer (P<0.05) plasma half-life, elimination half-life, and area under the curve (AUC) value compared with IR820, indicating larger overall exposure to the theranostic agent in mice. The IRPDcov conjugate had different organ localization than did free IR820, with potential reduced accumulation in the kidneys and significantly lower (P<0.05) accumulation in the lungs. Some potential advantages of IR820-PEG-diamine nanoconjugates may include passive targeting of tumor tissue through the enhanced permeability and retention effect, prolonged circulation times resulting in increased windows for combined diagnosis and therapy, and further opportunities for functionalization, targeting, and customization. The conjugation of PEG-diamine with a near-infrared dye provides a multifunctional delivery vector whose localization can be monitored with noninvasive techniques and that may also serve for guided hyperthermia cancer treatments.

Rapid and effective sample clean-up based on magnetic multiwalled carbon nanotubes for the determination of pesticide residues in tea by gas chromatography-mass spectrometry.

In this work, amine-functionalised magnetic nanoparticles and multiwalled carbon nanotubes (MNPs/MWCNTs) composites were synthesised by a simple method and applied as an adsorbent for rapid clean-up of acetonitrile extracts of tea samples prior to analysing eight pesticide residues by gas chromatography-mass spectrometry. Several parameters affecting the sampling and treatment efficiency were investigated, including extraction solvent, sonication time, weight ratio of MWCNTs to MNPs in the composites, amount of adsorbent, clean-up time and washing solution. Under the optimised conditions, the recoveries obtained for each pesticide ranged from 72.5% to 109.1% with relative standard deviations lower than 12.6%. Limit of quantification ranged from 0.02 to 0.08 mg kg⁻¹. The established method was successfully applied to the analysis of pesticide residues in real tea samples. The results indicated that the use of MNPs/MWCNTs composites allowed the simple and expeditious clean-up of complex tea samples for subsequent determination of pesticide residues.

Ion mobility spectrometry for monitoring diamine oxidase activity.

The capability of IMS for the determination of kinetics in complex enzyme systems with reduced v(max) values has been demonstrated with the example of diamine oxidase (DAO). Michaelis-Menten and Lineweaver-Burk plots were obtained for the enzyme catalyzed putrescine oxidation and calculations of the kinetic parameters have been performed and compared with previously published values. The IMS procedure provided a limit of detection of 200 pg mL(-1) for putrescine, a limit of quantification of 667 pg mL(-1), a precision of 5.9%, and an analysis frequency of 40 s, which are analytical characteristics appropriate to perform label-free enzyme studies. Additionally, pseudo-competitive inhibition of the putrescine oxidation due to other diamines binding to the free enzyme has been evaluated. Moreover, the mass-mobility correlation curve of diamines based on the calculated mobilities of the studied analytes and data previously reported for cadaverine, serotonin and tryptamine was modelled. The analytical method could be used as an additional complementary tool for the existing drug discovery method, for the search of DAO activators; molecules that displace the substrate from the second site of DAO, but does not interfere with the catalytic function of the first site.

A new orally active, aminothiol radioprotector-free of nausea and hypotension side effects at its highest radioprotective doses.

PURPOSE: A new aminothiol, PrC-210, was tested for orally conferred radioprotection (rats, mice; 9.0 Gy whole-body, which was otherwise lethal to 100% of the animals) and presence of the debilitating side effects (nausea/vomiting, hypotension/fainting) that restrict use of the current aminothiol, amifostine (Ethyol, WR-2721). METHODS AND MATERIALS: PrC-210 in water was administered to rats and mice at times before irradiation, and percent-survival was recorded for 60 days. Subcutaneous (SC) amifostine (positive control) or SC PrC-210 was administered to ferrets (Mustela putorius furo) and retching/emesis responses were recorded. Intraperitoneal amifostine (positive control) or PrC-210 was administered to arterial cannulated rats to score drug-induced hypotension. RESULTS: Oral PrC-210 conferred 100% survival in rat and mouse models against an otherwise 100% lethal whole-body radiation dose (9.0 Gy). Oral PrC-210, administered by gavage 30-90 min before irradiation, conferred a broad window of radioprotection. The comparison of PrC-210 and amifostine side effects was striking because there was no retching or emesis in 10 ferrets treated with PrC-210 and no induced hypotension in arterial cannulated rats treated with PrC-210. The tested PrC-210 doses were the ferret and rat equivalent doses of the 0.5 maximum tolerated dose (MTD) PrC-210 dose in mice. The human equivalent of this mouse 0.5 MTD PrC-210 dose would likely be the highest PrC-210 dose used in humans. By comparison, the mouse 0.5 MTD amifostine dose, 400 µg/g body weight (equivalent to the human amifostine dose of 910 mg/m(2)), when tested at equivalent ferret and rat doses in the above models produced 100% retching/vomiting in ferrets and 100% incidence of significant, progressive hypotension in rats. CONCLUSIONS: The PrC-210 aminothiol, with no detectable nausea/vomiting or hypotension side effects in these preclinical models, is a logical candidate for human drug development to use in healthy humans in a wide variety of radioprotection settings, including medical radiation, space travel, and nuclear accidents.

Antiviral stilbene 1,2-diamines prevent initiation of hepatitis C virus RNA replication at the outset of infection.

The recent development of a cell culture model of hepatitis C virus (HCV) infection based on the JFH-1 molecular clone has enabled discovery of new antiviral agents. Using a cell-based colorimetric screening assay to interrogate a 1,200-compound chemical library for anti-HCV activity, we identified a family of 1,2-diamines derived from trans-stilbene oxide that prevent HCV infection at nontoxic, low micromolar concentrations in cell culture. Structure-activity relationship analysis of ~ 300 derivatives synthesized using click chemistry yielded compounds with greatly enhanced low nanomolar potency and a > 1,000:1 therapeutic ratio. Using surrogate models of HCV infection, we showed that the compounds selectively block the initiation of replication of incoming HCV RNA but have no impact on viral entry, primary translation, or ongoing HCV RNA replication, nor do they suppress persistent HCV infection. Selection of an escape variant revealed that NS5A is directly or indirectly targeted by this compound. In summary, we have identified a family of HCV inhibitors that target a critical step in the establishment of HCV infection in which NS5A translated de novo from an incoming genomic HCV RNA template is required to initiate the replication of this important human pathogen.

9'-Epi-3ß,3'ß-dimethylxestospongin C, a new macrocyclic diamine alkaloid from the Hainan sponge Neopetrosia exigua.

A new BIS-1-oxaquinolizidine alkaloid, 9'- EPI-3 ß,3' ß-dimethylxestospongin C (2), and three known related analogues have been isolated from the Hainan sponge Neopetrosia exigua.

Catalytic asymmetric direct Mannich reaction: a powerful tool for the synthesis of alpha,beta-diamino acids.

Optically active alpha,beta-diamino acids are very attractive targets in organic synthesis because of their wide-ranging biological significance and high versatility as synthetic building blocks. Efficient synthesis of such non-proteinogenic amino acid derivatives must face the challenge of generating two contiguous stereocenters with complete diastereo- and enantiocontrol in flexible, acyclic molecules. The catalytic asymmetric direct Mannich reaction has provided elegant and efficient solutions for the stereocontrolled assembly of both syn- and anti-alpha,beta-diamino acid derivatives, including those with a alpha-tetrasubstituted carbon stereocenter, with the aid of either organometallic or purely organic chiral catalysts (or the combination of both). This tutorial review highlights progress in this area, which has recently been boosted through two complementary strategies: the direct Mannich reaction of glycine ester Schiff bases with imines and the direct aza-Henry reaction between nitro compounds and imines.

Recent advances in the preclinical evaluation of the topical antibacterial agent REP8839.

REP8839 is a synthetic fluorovinylthiophene-containing diaryldiamine that inhibits bacterial methionyl tRNA synthetase (MetRS) and is a new chemical entity that represents a novel pharmacological class. The compound has potent in vitro antibacterial activity against many clinically important Gram-positive bacteria including the major skin pathogens Staphylococcus aureus and Streptococcus pyogenes. In light of the emergence of methicillin-resistant S. aureus in the community and increasing resistance to mupirocin, REP8839 is being evaluated as a topical agent for the treatment of superficial skin infections. REP8839 was active against resistant phenotypes of S. aureus and can be formulated at high concentrations to minimize the development of resistance. A formulation of REP8839 has demonstrated efficacy in a porcine partial thickness wound infection model against mupirocin-resistant S. aureus.

Catalytic asymmetric allylic and homoallylic diamination of terminal olefins via formal C-H activation.

This paper describes a catalytic asymmetric diamination process for terminal olefins at allylic and homoallylic carbons via formal C-H activation using di-tert-butyldiaziridinone as nitrogen source with a catalyst generated from Pd2(dba)3 and chiral phosphorus amidite ligand. A wide variety of readily available terminal olefins can be effectively diaminated in good yields with high regio-, diastereo-, and enantioselectivities.

Structure-activity relationships of methoctramine-related polyamines as muscarinic antagonist: effect of replacing the inner polymethylene chain with cyclic moieties.

The aim of the present paper was to investigate the role of the octamethylene spacer of methoctramine (1) on the biological profile. Thus, this spacer was incorporated into a dianiline or dipiperidine moiety to determine whether flexibility and the basicity of the inner nitrogen atoms are important determinants of potency with respect to muscarinic receptors. The most potent compound was 4, which displayed, in the functional assays, a comparable potency at muscarinic M(2) receptors with respect to 1, and, in the binding assays, a loss of potency and selectivity toward muscarinic M(1) and M(3) receptor subtypes. Both compounds were endowed with antinociceptive activity. Furthermore, in microdialysis tests in rat parietal cortex, they enhanced acetylcholine release, most likely by antagonizing presynaptic muscarinic receptor subtypes.

Novel supramolecular assembly of symmetrical mixed-metal-ligand complexes of dioxouranium(VI).

Some binary and ternary novel complexes of dioxouranium(VI) with 8-hydroxy-7-quinolinecarboxaldehyde (OXH) have been prepared and characterized by elemental analyses, magnetic susceptibility measurements and spectral studies. Coordination effects on the vibrational spectra of the ligands have been investigated. The amine exchange reactions of coordinated Schiff bases in these complexes have been also studied, which reveal symmetrical tetradentate Schiff base complexes. Metal exchange reaction of dioxouranium(VI) complexes was obtained when reacted with tetradentate Schiff base complexes of Cu(II) with ZrCl(4)/UO(2)(CH(3)COO)(2) giving heterobinuclear complexes. Magnetic, electronic and IR spectral data suggest the configurations of distorted square planar ligand field copper(II) complexes. The ligands behave as bi-(O,O) and tetradentate (N(2),O(2)) donors. El-Sonbati equation has been used to evaluate the symmetric stretching frequency from which the F(U-O) and F(UO,UO)(-) were calculated. The bond distances of these complexes were also investigated.

Optimization of the modification of carrier proteins with aminated haptens.

In this report we show that succinic groups are far more reactive to amino compounds than the carboxylic groups derived from Asp and Glu on the protein when using coupling via 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI) (even by an 8 fold factor). Accordingly, a new carrier-protein was designed where both natural amino and carboxylic moieties were transformed into succinic residues. To prepare this hypersuccinylated carrier, all exposed carboxylic acids were first transformed into amino groups by reaction with ethylendiamine after activation with EDCI. Secondly, all these residues together with the ones from Lys were succinylated to prepare a fully succinylated protein. This was even more relevant considering that the amount of Lysine was 2-4 fold lower than Asp and Glu in most of the proteins. These "hyper-succinylated" proteins (KLH or BSA) offer significant improvements in protein reactivity compared to the native proteins (by a factor of 8-10). The optimization of the reaction, in which the presence of dioxane was found to be influential, permitted further improvements in the modification of the protein. Finally, this new strategy was successfully used to develop antibodies against the commercial anti-tumor molecule, ET-637-NH2. Using native KLH no response was found, whereas 1/64,000 serum dilutions gave very high values in ELISA procedures when immunization was performed using the hyper-succinylated KLH.