Synthesis of Arylated Benzofurans by Regioselective Suzuki–Miyaura Cross‐Coupling Reactions of 2,3‐Dibromobenzofurans‐ and 2,3,5‐Tribromobenzofurans

Arylated benzofurans were prepared by regioselective Suzuki–Miyaura cross‐coupling reactions of 2,3‐dibromobenzofuran. The reactions proceeded with very good site‐selectivity in favor of the more electron deficient position 2. The Suzuki–Miyaura reactions of 2,3,5‐tribromobenzofuran also proceeded in favor of position 2.     

Synthesis of functionalized arylpyridines and -pyrimidines by domino [4+2]/retro [4+2] cycloadditions of electron-rich dienes with alkynylpyridines and -pyrimidines

Aryl-substituted pyridines and pyrimidines were prepared by [4+2] cycloadditions of alkynyl-substituted pyridines and -pyrimidines with electron-rich dienes. The reactions proceed by formation of a bridged cycloadduct and subsequent thermal extrusion of ethylene. The pyridine moiety plays a crucial role for the success of the reaction.     

Radiolabeled Nanogels for Nuclear Molecular Imaging

An efficient and simple synthesis approach to form stable ⁶⁸Ga‐labeled nanogels is reported and their fundamental properties investigated. Nanogels are obtained by self‐assembly of amphiphilic statistical prepolymers derivatised with chelating groups for radiometals. The resulting nanogels exhibit a well‐defined spherical shape with a diameter of 290 ± 50 nm. The radionuclide ⁶⁸Ga is chelated in high radiochemical yields in an aqueous medium at room temperature. The phagocytosis assay demonstrates a highly increased internalization of nanogels by activated macrophages. Access to these ⁶⁸Ga‐nanogels will allow the investigation of general behavior and clearance pathways of nanogels in vivo by nuclear molecular imaging.

     

Metabolite assignment of ultrafiltered synovial fluid extracted from knee joints of reactive arthritis patients using high resolution NMR spectroscopy

Currently, there are no reliable biomarkers available that can aid early differential diagnosis of reactive arthritis (ReA) from other inflammatory joint diseases. Metabolic profiling of synovial fluid (SF)—obtained from joints affected in ReA—holds great promise in this regard and will further aid monitoring treatment and improving our understanding about disease mechanism. As a first step in this direction, we report here the metabolite specific assignment of ¹H and ¹³C resonances detected in the NMR spectra of SF samples extracted from human patients with established ReA. The metabolite characterization has been carried out on both normal and ultrafiltered (deproteinized) SF samples of eight ReA patients (n = 8) using high-resolution (800 MHz) ¹H and ¹H─¹³C NMR spectroscopy methods such as one-dimensional ¹H CPMG and two-dimensional J-resolved¹H NMR and homonuclear ¹H─¹H TOCSY and heteronuclear¹H─¹³C HSQC correlation spectra. Compared with normal SF samples, several distinctive ¹H NMR signals were identified and assigned to metabolites in the ¹H NMR spectra of ultrafiltered SF samples. Overall, we assigned 53 metabolites in normal filtered SF and 64 metabolites in filtered pooled SF sample compared with nonfiltered SF samples for which only 48 metabolites (including lipid/membrane metabolites as well) have been identified. The established NMR characterization of SF metabolites will serve to guide future metabolomics studies aiming to identify/evaluate the SF-based metabolic biomarkers of diagnostic/prognostic potential or seeking biochemical insights into disease mechanisms in a clinical perspective.     

Determination of metabolic profile of anti-malarial trioxane CDRI 99/411 in rat liver microsomes using HPLC

CDRI 99/411 is a potent 1,2,4‐trioxane anti‐malarial candidate compound of the Central Drug Research Institute, India. This study aimed to conduct comprehensive in vitro metabolic investigations of CDRI 99/411 to corroborate its preclinical investigations. Preliminary in vitro metabolic investigations were performed to assess the metabolic stability [in vitro half‐life (t_1/2) and in vitro hepatic intrinsic clearance (Cl_int)] of CDRI 99/411 in male Sprague–Dawley rat and human liver microsomes using validated high‐performance liquid chromatography with photodiode array detector. The observed in vitro t_1/2 of the compound in rat and human liver microsomes was 13 min with in vitro Cl_int 130.7 ± 25.0 μL/min/mg and 19 min with in vitro Cl_int 89.3 ± 17.40 μL/min/mg. These observations suggested moderate metabolic degradation and in vitro Cl_int with insignificant difference (p > 0.05) in the metabolic stability profile in rat and human. Hence, in vitro metabolic investigations were performed with rat liver microsomes. It was observed that CDRI 99/411 exhibited sigmoidal kinetics. At nonlinear regression (r ≥ 0.99) EC₅₀ and Hill slope values were 17 µm and 1.50, respectively. The metabolism of CDRI 99/411 was primarily mediated by CYP3A2 and was inferred by CYP reaction phenotyping with known potent inhibitors. Two metabolites of CDRI 99/411 were detected which were undetectable on incubation with 1‐aminobenzotriazole and ketoconazole. Copyright © 2011 John Wiley & Sons, Ltd.     

Infrared optical imaging of matrix metalloproteinases (MMPs) up regulation following ischemia reperfusion is ameliorated by hypothermia

Background

Continuous theta burst stimulation (cTBS) is a form of repetitive transcranial magnetic stimulation which has been shown to alter cortical excitability in the upper limb representation of primary somatosensory cortex (SI). However, it is unknown whether cTBS modulates cortical excitability within the lower limb representation in SI. The present study investigates the effects of cTBS over the SI lower limb representation on cortical somatosensory evoked potentials (SEPs) and Hoffmann reflex (H-reflex) following tibial nerve stimulation at the knee. SEPs and H-reflex were recorded before and in four time blocks up to 30 minutes following cTBS targeting the lower limb representation within SI.

Results

Following cTBS, the P1-N1 first cortical potential was significantly decreased at 12?C16 minutes. CTBS also suppressed the P2-N2 second cortical potential for up to 30 minutes following stimulation. The H-reflex remained statistically unchanged following cTBS although there was a modest suppression observed.

Conclusion

We conclude that cTBS decreases cortical excitability of the lower limb representation of SI as evidenced by suppressed SEP amplitude. The duration and magnitude of the cTBS after effects are similar to those observed in upper limb studies.     

Mono- and bisphenoxy derivatives of bis(indenyl)zirconium(IV)

A series of (C₉H₇)₂Zr(OAr)Cl and (C₉H₇)₂Zr(OAr)₂ complexes, where Ar = C₆H₅, p-ClC₆H₄, α-C₁₀H₇, or β-C₁₀H₇, have been synthesised by the reaction of bis(indenyl)zirconium(IV)-dichloride with an appropriate phenol in a 1:1 and 1:2 molar ratio in refluxing benzene in the presence of triethylamine. These complexes have been characterised by elemental analyses, conductance measurements and spectral (IR, ¹H NMR and electronic) studies.     

Cyclodextrin-mediated regioselective photo-Fries reaction of 1-naphthyl phenyl acylates

1-Naphthyl phenyl acylates upon irradiation in solution yield eight products via β-cleavage process. However, excitation of these molecules as included in γ-cyclodextrin results in a single product (>95%). This medium dependent product selectivity is attributed to conformational and translational restrictions enforced on the reactant as well as intermediates by the cyclodextrin cavity.     

Salicylaldehydo chelates of bis(cyclopentadienyl) zirconium(IV)

A new series of organometallic ionic chelates of the type [Cp ₂Zr(sal)]⁺ [ROCS₂/RRNCS₂]^–, where Hsal = salicylaldehyde;R =Me, Et, i-Pr ori-Bu andR =R =Me, Et, i-Pr;R =Me,R = benzyl orR =Et,R =m-tolyl, have been synthesized in aqueous medium by the reaction of [Cp ₂Zr(sal)]⁺Cl^– andROCS ₂ ^– K⁺/RRNCS ₂ ^– Na⁺. These compounds have been characterized by chemical analyses, electrical conductance, electronic, IR and¹H-NMR spectral studies. These studies indicate that the complexes are 1:1 electrolytes and the salicylaldehyde ligand is chelating in all these complexes. Therefore, a tetrahedral coordination about the zirconium atom is proposed.

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Salicylaldehydo-Chelate von Bis(cyclopentadienyl)-zirkonium(IV)

Zusammenfassung Eine neue Gruppe von organometallischen ionischen Chelaten vom Typ [Cp ₂Zr(sal)]⁺ [ROCS₂/RRNCS₂]^– (mit Hsal = Salicyladehyd;R =Me, Et, i-Pr oderi-Bu undR =R =Me, Et, i-Pr;R =Me,R = Benzyl oderR =Et,R =m-Tolyl) wurde in wäßrigem Medium mittels der Reaktion von [Cp ₂Zr(sal)]⁺Cl^– mitROCS ₂ ^– K⁺/RRNCS ₂ ^– Na⁺ hergestellt. Die erhaltenen Verbindungen wurden mittels chemischer Analyse, elektrischer Leitfähigkeit und der IR- sowie¹H-NMR-Spektren charakterisiert. Diese Untersuchungen zeigen, daß die Komplexe 1:1-Elektrolyte sind, wobei der Salicylaldehyd-Ligand in allen Fällen an der Chelatbildung beteiligt ist. Es wird daher für das Zirkoniumatom eine tetrahedrale Koordination vorgeschlagen.