A tandem enyne/ring closing metathesis approach to 4-methylene-2-cyclohexenols: an efficient entry to otteliones and loloanolides

A short and efficient approach to a 4-methylene-2-cyclohexenone substructure present in otteliones and loloanolides is described. This strategy involves a tandem enyne/ring closing metathesis as the key reaction to construct this labile core unit.     

Silica supported lanthanum triflate mediated synthesis of 5-substituted-1H tetrazoles

Silica supported lanthanum triflate (Ln(OTf)₃-SiO₂) promoted synthesis of 5-substituted 1H-tetrazoles via [3+2] cycloaddition between aromatic/heteroaromatic nitriles and sodium azide is a high product yielding, facile, and straightforward procedure. Non toxicity, recovery, and reusability for three continuous cycles are the noteworthy features of the currently employed heterogeneous catalyst.     

A Stability-Indicating LC Method for Lumefantrine

A simple, rapid, and precise method is developed for the quantitative determination of lumefantrine (Lume) in active pharmaceutical ingredient (API). A chromatographic separation of Lume and its degradants were achieved with an X-Terra RP18, 250 × 4.6 mm, and 5 μ analytical column using buffer–acetonitrile (30:70 v/v). The buffer used in mobile phase contains 0.1 M sodium perchlorate monohydrate in double distilled water pH adjusted to 2.1 with trifluoroacetic acid. The instrumental settings are flow rate of 0.5 mL (L), column temperature at 35 °C, and detector wavelength of 235 nm using a photodiode array detector. Lume was exposed to thermal, photolytic, hydrolytic and oxidative stress conditions, and the stressed samples were analysed by the proposed method. Peak homogeneity data of Lume obtained by photodiode array detection, in the stressed sample chromatograms, demonstrated the specificity of the method for estimation in the presence of degradants. The described method shows excellent linearity over a range of 10–200 μg L⁻¹ for Lume. The correlation coefficient is 1. The relative standard deviation of peak area for six measurements is always less than 2% between days. The proposed method was found to be suitable and accurate for quantitative determination and stability study of Lume in API.

     

Design of segmented cladding fiber for femtosecond laser pulse delivery at 1550 and 1064 nm wavelengths

Segmented cladding fiber (SCF) is capable of single mode operation over an extended range of wavelengths while maintaining large mode area. In this paper we report the design of an SCF with mode area as large as 1,825  $\upmu \hbox {m}^{2}$ , suitable for delivery of high peak power femtosecond laser pulses at 1550 and 1064 nm wavelengths. An SCF with such a large-mode area is a few-moded fiber and its design requires careful choice of design parameters to have robustness against mode-coupling effects and bend loss. In this paper we address these issues and report a design of an SCF showing near distortion-free propagation of 100-fs, 53-kW peak power pulses at 1550-nm wavelength with 1,825- $\upmu \hbox {m}^{2}$ mode area through fundamental mode. The same fiber can also deliver 250-fs, 15-kW peak power pulses at 1064-nm wavelength with 1,793- $\upmu \hbox {m}^{2}$ mode area. The fiber has been analyzed by using the radial effective-index method in conjunction with transfer matrix method and the pulse propagation has been studied by solving the nonlinear Schroedinger equation by split-step Fourier method. Such a fiber would find applications in multiphoton microscopy and in biomedical engineering.     

Derivative free method for computing modes of multilayer planar waveguide

A technique to solve generalized dispersion equation of multilayer planar waveguide has been demonstrated to obtain all the expected guided modes. The solution is based on the derivative free method for computing the zeros of an analytical function in complex plane. The derivative free method extracts the roots which are very close to actual zeros of the function. Roots are further refined using the robust iteration method to achieve the desired accuracy. Application of the proposed method has been verified by solving the modes of a variety of structures including lossless structure, leaky structure, quantum well waveguide, active waveguide, ARROW waveguide and metal clad waveguide. The method is efficient and computes all modes of planar waveguide with high accuracy.     

Incurred sample reanalysis in drug discovery bioanalysis

Bioanalysis plays a key role during the drug discovery process to generate the pharmacokinetic data to facilitate unbiased evaluation of leads, optimized leads and drug candidates. Such pharmacokinetic data are used to enable key decisions in the drug discovery process. The aim of the work is to put forward a new strategy of performing the incurred sample reanalysis for select small molecule novel chemical entities at different stages of drug discovery prior to candidate selection. Three discovery programs representing hits, leads and optimized lead candidates were selected for the incurred sample reanalysis (ISR) analysis. From each discovery program, two novel chemical entities were selected for the ISR analysis. The time points considered for ISR generally varied among the programs; however, samples coinciding with drug absorption, distribution and elimination were considered in the ISR assessment. With the exception of a single ISR value that gave a high deviation (about 63%), the observed ISR values supported the discovery bioanalytical assays. While the individual bioanalytical laboratory can draw an algorithm for selecting novel chemical entities and fixing the acceptance criteria for the ISR data, it is proposed that the percentage difference between ISR vs. original concentration for 67% of the repeat samples is contained within ±30% for discovery bioanalysis.     

Quantitative FRET (qFRET) Technology for the Determination of Protein–Protein Interaction Affinity in Solution

Protein–protein interactions play pivotal roles in life, and the protein interaction affinity confers specific protein interaction events in physiology or pathology. Förster resonance energy transfer (FRET) has been widely used in biological and biomedical research to detect molecular interactions in vitro and in vivo. The FRET assay provides very high sensitivity and efficiency. Several attempts have been made to develop the FRET assay into a quantitative measurement for protein–protein interaction affinity in the past. However, the progress has been slow due to complicated procedures or because of challenges in differentiating the FRET signal from other direct emission signals from donor and receptor. This review focuses on recent developments of the quantitative FRET analysis and its application in the determination of protein–protein interaction affinity (K_D), either through FRET acceptor emission or donor quenching methods. This paper mainly reviews novel theatrical developments and experimental procedures rather than specific experimental results. The FRET-based approach for protein interaction affinity determination provides several advantages, including high sensitivity, high accuracy, low cost, and high-throughput assay. The FRET-based methodology holds excellent potential for those difficult-to-be expressed proteins and for protein interactions in living cells.     

Identification of metabolites of novel Anti‐MRSA fluoroquinolone WCK 771 in mouse,rat, rabbit,dog, monkey and human urine using liquid chromatography tandem mass spectrometry

WCK 771 is an l ‐arginine salt of levonadifloxacin (LND) being developed in intravenous dosage form and has recently completed a phase III trial in India. The pharmacokinetics of WCK 771, a novel anti‐MRSA fluoroquinolone, were examined in mice, rats, rabbits, dogs, monkeys and humans after systemic administration during pre‐clinical and clinical investigations. Urine and serum were evaluated for identification of metabolites. It was observed that LND mainly follows phase II biotransformation pathways. All of the species showed a different array of metabolites. In mice, rabbit and dog, the drug was mainly excreted in the form of O‐glucuronide (M7) and acyl glucuronide (M8) conjugates, whereas in rat and human major metabolite was sulfate conjugate (M6). Monkeys exhibited equal distribution of sulfate (M6) and glucuronide conjugates (M7, M8). In addition to these three major phase II metabolites; five phase I oxidative metabolites (M1, M2, M3, M4 and M5) were identified using liquid chromatography tandem mass spectrometry. Out of these eight metabolites M2, M3, M5, M7 and M8 are reported for the first time.     

3D printed titanium micro-bore columns containing polymer monoliths for reversed-phase liquid chromatography

The potential of 3D selective laser melting (SLM) technology to produce compact, temperature and pressure stable titanium alloy chromatographic columns is explored. A micro bore channel (0.9 mm I.D. × 600 mm long) was produced within a 5 × 30 × 30 mm titanium alloy (Ti–6Al–4V) cuboid, in form of a double handed spiral. A poly(butyl methacrylate-co-ethyleneglycoldimethacrylate) (BuMA-co-EDMA) monolithic stationary phase was thermally polymerised within the channel for application in reversed-phase high-performance liquid chromatography. The prepared monolithic column was applied to the liquid chromatographic separation of intact proteins and peptides. Peak capacities of 69–76 (for 6–8 proteins respectively) were observed during isothermal separation of proteins at 44 °C which were further increased to 73–77 using a thermal step gradient with programmed temperature from 60 °C to 35 °C using an in-house built direct-contact heater/cooler platform based upon matching sized Peltier thermoelectric modules. Rapid temperature gradients were possible due to direct-contact between the planar metal column and the Peltier module, and the high thermal conductivity of the titanium column as compared to a similar stainless steel printed column. The separation of peptides released from a digestion of E.coli was also achieved in less than 35 min with ca. 40 distinguishable peaks at 210 nm.     

UV-switchable polyoxometalate sandwiched between TiO2 and metal nanoparticles for enhanced visible and solar light photococatalysis

To improve the photocatalytic efficiency of TiO(2)-based nanomaterials, we demonstrate a facile, generalized, highly localized reduction approach to the decoration of TiO(2)-polyoxometalate composites with a range of metal nanoparticles including Cu, Ag, Pt, and Au. The synthesis of nanocomposite photococatalysts reported in this study has been achieved by utilizing the unique ability of the TiO(2)-bound PTA (phosphotungstic acid) molecules (a polyoxometalate, POM) to act as a highly localized UV-switchable reducing agent that specifically reduces metal ions to their nanoparticulate forms directly and only onto the TiO(2) surface. This leads to the metal contaminant-free synthesis of TiO(2)-PTA-metal nanocomposites, which is a significant advantage of the proposed approach. The study further demonstrates that polyoxometalates are regenerable photoactive molecules with outstanding electron-transfer ability and the deposition of metal nanoparticles on the TiO(2)-PTA cocatalytic surface can have a dramatic effect on increasing the overall photocatalytic performance of the composite system. Moreover, it is observed that the photococatalytic performance of the TiO(2)-PTA-metal nanoparticles can be fine tuned by choosing the composition of metal nanoparticles in the nanocomposite. Interestingly, the photococatalysts reported here are found to be active under visible and simulated solar-light conditions. The underlying reaction mechanism for enhanced solar-light photococatalysis has been proposed.