Profiling primaquine metabolites in primary human hepatocytes using UHPLC‐QTOF‐MS with 13C stable isotope labeling

Therapeutic efficiency and hemolytic toxicity of primaquine (PQ), the only drug available for radical cure of relapsing vivax malaria are believed to be mediated by its metabolites. However, identification of these metabolites has remained a major challenge apparently due to low quantities and their reactive nature. Drug candidates labeled with stable isotopes afford convenient tools for tracking drug‐derived metabolites in complex matrices by liquid chromatography‐tandem mass spectrometry (LC‐MS‐MS) and filtering for masses with twin peaks attributable to the label. This study was undertaken to identify metabolites of PQ from an in vitro incubation of a 1:1 w/w mixture of ¹³C₆‐PQ/PQ with primary human hepatocytes. Acquity ultra‐performance LC (UHPLC) was integrated with QTOF‐MS to combine the efficiency of separation with high sensitivity, selectivity of detection and accurate mass determination. UHPLC retention time, twin mass peaks with difference of 6 (originating from ¹³C₆‐PQ/PQ), and MS‐MS fragmentation pattern were used for phenotyping. Besides carboxy‐PQ (cPQ), formed by oxidative deamination of PQ to an aldehyde and subsequent oxidation, several other metabolites were identified: including PQ alcohol, predictably generated by oxidative deamination of PQ to an aldehyde and subsequent reduction, its acetate and the alcohol's glucuronide conjugate. Trace amounts of quinone‐imine metabolites of PQ and cPQ were also detected which may be generated by hydroxylation of the PQ/cPQ quinoline ring at the 5‐position and subsequent oxidation. These findings shed additional light on the human hepatic metabolism of PQ, and the method can be applied for identification of reactive PQ metabolites generated in vivo in preclinical and clinical studies. Copyright © 2013 John Wiley & Sons, Ltd.     

Simple and Selective Removal of the t‐Butyloxycarbonyl (Boc) Protecting Group on Indoles,Pyrroles, Indazoles,and Carbolines

A highly selective and efficient deprotection of the N‐t‐butoxy carbonyl (N‐Boc) group on indoles, pyrroles, indazoles, and carbolines has been achieved in high yields using a catalytic amount of NaOMe as a base in dry MeOH, at ambient temperature.     

Bismuth triflate catalyzed conjugate addition of indoles to α,β-enones

Reaction of indoles with electron deficient olefins under the influence of bismuth triflate has been studied at ambient temperature and affords the corresponding 3-alkylated indoles in excellent yields.     

Cadmium Chloride (CdCl2): An Efficient Catalyst for Conjugate Addition of Amines to Electron‐Poor Alkenes

Electron‐deficient olefins undergo rapid Aza–Michael reaction with a wide range of amines catalyzed by cadmium chloride at room temperature.     

Enhanced cubic optical nonlinearity of oligoazine derivatives

We report a large positive third-order optical nonlinearity of synthesized oligoazine derivatives (OADs) using z-scan technique at 532 nm by Q-switched Nd:YAG laser. Optical band gap of OADs shrinks with increasing repeated units. Origin of large cubic nonlinearity is in the extensive π-electron delocalization. We obtained the values of $\chi_{R}^{(3)} \approx (0.78 - 3.98) \times 10^{ - 11} \,{\text{esu}}$ and $\chi_{I}^{(3)} \approx (0.21 - 1.95) \times 10^{ - 11} \,{\text{esu}}$ in OADs. Moreover, values of optical nonlinearity of OADs show reasonable agreement with the theoretically predicted values. We have shown OADs could be used as good reverse saturable absorber and self-focusing materials. Optical limiting, due to reverse saturable absorption, has also been successfully demonstrated at 532 nm.     

Protein extraction and cytotoxicity abilities of colloidal gold-coated silica hybrid nanoparticles

Monodisperse non-hybrid silica and hybrid colloidal silica of ≤?200 nm decorated with small Au nanoparticles (NPs) were synthesized in a simple single-step method. Non-hybrid silica NPs were synthesized in the absence and presence of different twin tail cationic surfactants, while tiny Au NPs were grown under in situ reaction conditions on non-hybrid silica synthesized previously by using cationic dextran. Bio-applicability and cytotoxicity of both hybrid as well as non-hybrid silica NPs were tested by using them for the extraction of protein fractions from complex aqueous protein solutions and treating them with blood cells, respectively. Both non-hybrid and hybrid silica NPs demonstrate excellent ability to extract proteins fractions predominantly of relatively low molecular masses, i.e., ~ 80 kDa. Extraction preferences between both kinds of silica became prominent when predominantly hydrophobic proteins such zein and rice proteins were used rather than mainly polar protein like BSA. Applicability for more complex biological fluid like serum indicated the competitive extractions among strongly versus weakly bound proteins. With significant bearing in in vivo conditions, hybrid silica was potentially toxic towards the blood cells in comparison to non-hybrid silica. It stems from the collective interactions of silica as well as nanometallic surfaces of Au NPs to interact with the blood cells causing hemolysis and hence may not be the suitable vehicles for drug release in systemic circulation.

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Three new ingol diterpenes from Euphorbia nivulia: evaluation of cytotoxic activity

The latex of Euphorbia nivulia afforded three new ingol diterpenes, 3-acetyl-8-methoxyl-7-angolyl-12-hydroxylingol (7), 3,12-diacetyl-7-hydroxy-8-methoxylingol (8), and 3,12-diacetyl-7-angolyl-8-hydroxylingol (9) along with five known ingol diterpenes 2-6 and a known triterpene cyclonivulinol (1). Their structures were established by means of spectroscopic analysis. Diterpenes 2-9 were evaluated for their cytotoxic activity.     

Fractal interpolation: a sequential approach

Fractal interpolation is a modern technique to fit and analyze scientific data. We develop a new class of fractal interpolation functions which converge to a data generating(original) function for any choice of the scaling factors. Consequently, our method offers an alternative to the existing fractal interpolation functions(FIFs). We construct a sequence of α-FIFs using a suitable sequence of iterated function systems(IFSs). Without imposing any condition on the scaling vector, we establish constrained interpolation by using fractal functions. In particular,the constrained interpolation discussed herein includes a method to obtain fractal functions that preserve positivity inherent in the given data. The existence of Cr-α-FIFs is investigated. We identify suitable conditions on the associated scaling factors so that α-FIFs preserve r-convexity in addition to the C~r-smoothness of original function.