BODIPY: A Highly Versatile Platform for the Design of Bimodal Imaging Probes

In molecular imaging, multimodal imaging agents can provide complementary information, for improving the accuracy of disease diagnosis or enhancing patient management. In particular, optical/nuclear imaging may find important preclinical and clinical applications. To simplify the preparation of dual‐labeled imaging agents, we prepared versatile monomolecular multimodal imaging probe (MOMIP) platforms containing both a fluorescent dye (BODIPY) and a metal chelator (polyazamacrocycle). One of the MOMIP was conjugated to a cyclopeptide (i.e., octreotide) and radiolabeled with ¹¹¹In. In vitro and in vivo studies of the resulting bioconjugate were conducted, highlighting the potential of these BODIPY‐based bimodal probes. This work also confirmed that the biovector and/or the bimodal probes must be chosen carefully, due to the impact of the MOMIP on the overall properties of the resulting imaging agent.     

From the N‐Heterocyclic Carbene‐Catalyzed Conjugate Addition of Alcohols to the Controlled Polymerization of (Meth)acrylates

Among various N‐heterocyclic carbenes (NHCs) tested, only 1,3‐bis(tert‐butyl)imidazol‐2‐ylidene (NHC^tBu) proved to selectively promote the catalytic conjugate addition of alcohols onto (meth)acrylate substrates. This rather rare example of NHC‐catalyzed 1,4‐addition of alcohols was investigated as a simple means to trigger the polymerization of both methyl methacrylate and methyl acrylate (MMA and MA, respectively). Well‐defined α‐alkoxy poly(methyl (meth)acrylate) (PM(M)A) chains, the molar masses of which could be controlled by the initial [(meth)acrylate]₀/[ROH]₀ molar ratio, were ultimately obtained in N,N‐dimethylformamide at 25 °C. A hydroxyl‐terminated poly(ethylene oxide) (PEO‐OH) macro‐initiator was also employed to directly access PEO‐b‐PMMA amphiphilic block copolymers. Investigations into the reaction mechanism by DFT calculations revealed the occurrence of two competitive concerted pathways, involving either the activation of the alcohol or that of the monomer by NHC^tBu.     

Sharper asset ranking from total drawdown durations

The total duration of drawdowns is shown to provide a moment-free, unbiased, efficient and robust estimator of Sharpe ratios both for Gaussian and heavy-tailed price returns. We then use this quantity to infer an analytic expression of the bias of moment-based Sharpe ratio estimators as a function of the return distribution tail exponent. The heterogeneity of tail exponents at any given time among assets implies that our new method yields significantly different asset rankings than those of moment-based methods, especially in periods large volatility. This is fully confirmed by using 20 years of historical data on 3449 liquid US equities.     

The porosity, acidity, and reactivity of dealuminated zeolite ZSM-5 at the single particle level: the influence of the zeolite architecture

A combination of atomic force microscopy (AFM), high‐resolution scanning electron microscopy (HR‐SEM), focused‐ion‐beam scanning electron microscopy (FIB‐SEM), X‐ray photoelectron spectroscopy (XPS), confocal fluorescence microscopy (CFM), and UV/Vis and synchrotron‐based IR microspectroscopy was used to investigate the dealumination processes of zeolite ZSM‐5 at the individual crystal level. It was shown that steaming has a significant impact on the porosity, acidity, and reactivity of the zeolite materials. The catalytic performance, tested by the styrene oligomerization and methanol‐to‐olefin reactions, led to the conclusion that mild steaming conditions resulted in greatly enhanced acidity and reactivity of dealuminated zeolite ZSM‐5. Interestingly, only residual surface mesoporosity was generated in the mildly steamed ZSM‐5 zeolite, leading to rapid crystal coloration and coking upon catalytic testing and indicating an enhanced deactivation of the zeolites. In contrast, harsh steaming conditions generated 5–50 nm mesopores, extensively improving the accessibility of the zeolites. However, severe dealumination decreased the strength of the Brønsted acid sites, causing a depletion of the overall acidity, which resulted in a major drop in catalytic activity.     

Violet-to-blue tunable emission of aryl-substituted dispirofluorene-indenofluorene isomers by conformationally-controllable intramolecular excimer formation

Two series of DiSpiroFluorene-IndenoFluorene (DSF-IF) positional isomers, namely dispiro[2,7-diarylfluorene-9',6,9',12-indeno[1,2-b]fluorenes], (1,2-b)-DSF-IFs 1 and dispiro[2,7-diarylfluorene-9',6,9',12-indeno[2,1-a]fluorenes], (2,1-a)-DSF-IFs 2 have been synthesized. These violet-to-blue fluorescent emitters possess a 3π-2spiro architecture, which combines via two spiro links two different indenofluorene cores, that is, (1,2-b)-IF or (2,1-a)-IF and 2,7-substituted-diaryl-fluorene units. Due to their different geometric profiles, the two families of positional isomers present drastically different properties. The marked difference observed between the properties of (1,2-b)-DSF-IF (1) and (2,1-a)-DSF-IF (2) is discussed in terms of intramolecular π-π interactions occurring in (2,1-a)-DSF-IF (2) leading to conformationally-controllable intramolecular excimer formation. Indeed, the original geometry of the (2,1-a)-DSF-IF (2) family, with face-to-face "aryl-fluorene-aryl" moieties, leads to remarkable excimer emission through intramolecular π-π interactions in the excited state. Furthermore, the emission wavelengths can be gradually modulated by the control of the steric hindrance between the adjacent substituted phenyl rings. Thus, through a comparative and detailed study of the (1)H NMR, electrochemical and photophysical properties of DSF-IFs 1 and 2, we have evidenced the intramolecular π-π interactions occurring between the two "aryl-fluorene-aryl" moieties in the ground state and in the excited state. These properties have been finally correlated to the spectacular conformational change modeled by density functional theory (DFT) calculations. Indeed, the two "aryl-fluorene-aryl" moieties switch from a staggered conformation in the ground state to an eclipsed conformation in the first excited state.     

Electrochemical behaviour and voltammetric sensitivity at arrays of nanoscale interfaces between immiscible liquids

Arrays of nanoscale interfaces between immiscible electrolyte solutions were formed using silicon nitride nanopore array membranes. Nanopores in the range from 75 nm radius down to 17 nm radius were used to form the nano-interfaces. It was found that the liquid organic phase electrolyte solution filled the pores so that inlaid nano-interfaces were formed with the aqueous phase. Cyclic voltammetry at these nano-interface arrays demonstrated steady-state behaviour at the larger interfaces but the voltammetric wave-shape became progressively worse as the interface size decreased. It was found that the ion transfer currents were ca. 50% of those expected based on theoretical calculations, which is attributed to overlap of diffusion zones at adjacent nano-interfaces. Here, the separation between adjacent nano-interfaces was 20-times the interface radius. The analytical sensitivity for ion transfer from the aqueous to the 1,6-dichlorohexane organic phase was estimated from calibration plots of current density versus concentration of aqueous tetraethylammonium cation. The sensitivity was in the range of 65 μA cm(-2) μM(-1) (at 75 nm radius interfaces) to 265 μA cm(-2) μM(-1) (at 17 nm radius interfaces). The sensitivity depended directly on the inverse of the nano-interface radius, implying that smaller interfaces will provide better sensitivity, due to the enhanced flux of analyte arising from convergent diffusion to smaller electrochemical interfaces.     

Synchrotron FTIR analysis of drug treated ovarian A2780 cells: an ability to differentiate cell response to different drugs?

Recently a new di-gold(I) organometallic complex [1,3-(Ph(3)PAu)(2)-C(6)H(4)] (KF0101) has been synthesised and found to exhibit cytotoxic activity in vitro. Subsequently it has been demonstrated that KF0101 shows little or no cross-resistance against a number of the cisplatin resistant ovarian cancer cell lines in vitro suggesting a different mode of action for the drug. In this study, syncrotron radiation infrared microspectroscopy (SR-IRMS) has been used on drug treated single A2780 cells in order to determine if this different mode of action can be identified spectroscopically. The aim of the study was to establish: (i) if single cell SR-IRMS could be used to give insight into the cellular response on treatment with different cytotoxic agents relative to non-treated cells (control) and (ii) that if the cytotoxic drugs elicit a different biochemical response these responses could be distinguished from each other. The most striking features obtained after Principal Components Analysis (PCA) of Resonant Mie Scattering (RMieS) corrected single cell spectra of drug treated ovarian A2780 cells are: (i) The spectra obtained for the control are quite heterogeneous and several hundred spectra are required to adequately define the nature of the control; (ii) after drug treatment at the IC50 level for 24 h with cisplatin, KF0101, methotrexate, paclitaxel or 5-fluorouracil the cell spectra, as represented on a PCA scores plot, generally concentrate in certain well defined areas of the control, there are however a small number of spectra that fall outside of the area defined by the control; and (iii) a differentiation between cell spectra obtained on treatment with different drugs is observed which fits well with different in vitro cell culture behaviour and a flow cytometry cell cycle analysis of the control and drug treated cells. Inspection of the loading plots shows that PC1 is essentially the same for all plots and reflects changes in cell biochemistry related to the cell cycle. PC2, however, on comparison of the control versus cisplatin or cisplatin versus KF0101 is indicative of differences induced by drug treatment and has been termed as cell cycle-plus behaviour. These data are shown to be consistent with that obtained using bench-top IRMS by averaging a number of single cell spectra and carrying out a PCA, but SR-IRMS offers more insight into how the drug is affecting the cell population. More importantly, this approach enables the influence of the cell cycle on both the control and drug treated samples to be taken into consideration when evaluating the drug-cell interaction.     

Highly sensitive routine method for urinary 3-hydroxybenzo[a]pyrene quantitation using liquid chromatography-fluorescence detection and automated off-line solid phase extraction

Many workers and also the general population are exposed to polycyclic aromatic hydrocarbons (PAHs), and benzo[a]pyrene (BaP) was recently classified as carcinogenic for humans (group 1) by the International Agency for Research on Cancer. Biomonitoring of PAHs exposure is usually performed by urinary 1-hydroxypyrene (1-OHP) analysis. 1-OHP is a metabolite of pyrene, a non-carcinogenic PAH. In this work, we developed a very simple but highly sensitive analytical method of quantifying one urinary metabolite of BaP, 3-hydroxybenzo[a]pyrene (3-OHBaP), to evaluate carcinogenic PAHs exposure. After hydrolysis of 10 mL urine for two hours and concentration by automated off-line solid phase extraction, the sample was injected in a column-switching high-performance liquid chromatography fluorescence detection system. The limit of quantification was 0.2 pmol L(-1) (0.05 ng L(-1)) and the limit of detection was estimated at 0.07 pmol L(-1) (0.02 ng L(-1)). Linearity was established for 3-OHBaP concentrations ranging from 0.4 to 74.5 pmol L(-1) (0.1 to 20 ng L(-1)). Relative within-day standard deviation was less than 3% and relative between-day standard deviation was less than 4%. In non-occupationally exposed subjects, median concentrations for smokers compared with non-smokers were 3.5 times higher for 1-OHP (p<0.001) and 2 times higher for 3-OHBaP (p<0.05). The two urinary biomarkers were correlated in smokers (ρ=0.636; p<0.05; n=10) but not in non-smokers (ρ=0.09; p>0.05; n=21).     

On-chip multi-electrochemical sensor array platform for simultaneous screening of nitric oxide and peroxynitrite

In this work we report on the design, microfabrication and analytical performances of a new electrochemical sensor array (ESA) which allows for the first time the simultaneous amperometric detection of nitric oxide (NO) and peroxynitrite (ONOO(-)), two biologically relevant molecules. The on-chip device includes individually addressable sets of gold ultramicroelectrodes (UMEs) of 50 μm diameter, Ag/AgCl reference electrode and gold counter electrode. The electrodes are separated into two groups; each has one reference electrode, one counter electrode and 110 UMEs specifically tailored to detect a specific analyte. The ESA is incorporated on a custom interface with a cell culture well and spring contact pins that can be easily interconnected to an external multichannel potentiostat. Each UME of the network dedicated to the detection of NO is electrochemically modified by electrodepositing thin layers of poly(eugenol) and poly(phenol). The detection of NO is performed amperometrically at 0.8 V vs. Ag/AgCl in phosphate buffer solution (PBS, pH = 7.4) and other buffers adapted to biological cell culture, using a NO-donor. The network of UMEs dedicated to the detection of ONOO(-) is used without further chemical modification of the surface and the uncoated gold electrodes operate at -0.1 V vs. Ag/AgCl to detect the reduction of ONOOH in PBS. The selectivity issue of both sensors against major biologically relevant interfering analytes is examined. Simultaneous detection of NO and ONOO(-) in PBS is also achieved.     

On the enantioselectivity of aziridination of styrene catalysed by copper triflate and copper-exchanged zeolite Y: consequences of the phase behaviour of enantiomeric mixtures of N-arene-sulfonyl-2-phenylaziridines

By synthesising S-2-phenyl-N-(4-nitrophenyl)aziridine from S-phenylglycinol, it has been demonstrated that the aziridination of styrene by [N-(4-nitrobenzenesulfonyl)imino]phenyliodinane (nosyliminophenyliodinane, PhINNs) in the presence of S,S-2,2'-isopropylidene-bis(4-phenyl-2-oxazoline), catalysed by copper(II) triflate in CH(3)CN solution or heterogeneously by CuHY, has predominantly an R-configuration. The enantioselectivity of the aziridination of styrene by [N-arenesulfonylimino]-phenyliodinanes catalysed by copper-exchanged zeolite Y (CuHY), in conjunction with a chiral bis-oxazoline ligand, has been re-examined. In the case of PhINNs, it is shown that the product mixture of enantiomeric aziridines, on treatment with hexane, gives rise to a solid phase of low enantiomeric excess (ee) and a solution phase of high ee. Separation of the solid phase and recrystallisation afforded a true racemate (racemic compound), which has been confirmed by X-ray crystallography. The aziridine obtained from the solution phase could be recrystallised to produce the pure enantiomer originally in excess. A consequence of the new findings is that previous reports on the enantioselectivity of copper-catalysed aziridination, both in heterogeneous and homogeneous conditions, should be regarded with caution if the analytical procedure involved HPLC with injection of the enantiomeric mixture in a hexane-rich solvent. Such a method has been used in previous work from this laboratory, but has also been used elsewhere, following the procedure developed by Evans and co-workers when the (homogeneous) copper-catalysed aziridination by PhINTs was first discovered. Evidently, the change of substituent in the benzenesulfonyl group reduces the solubility in hexane, affording a solution phase of enhanced ee.