Microscopic modes and free energies of 3-phosphoinositide-dependent kinase-1 (PDK1) binding with celecoxib and other inhibitors

Celecoxib, also known as Celebrex (approved by FDA in 1998) and remembered as the fastest-selling drug in history, was used as a cyclooxygenase-2 (COX-2) selective inhibitor having both anti-inflammatory and anticancer activities. Most recent studies have revealed that the apoptotic activity of celecoxib (and its derivatives) is actually independent of the COX-2 inhibitory activity and that celecoxib also inhibits the kinase activity of 3-phosphoinositide-dependent protein kinase-1 (PDK1), suggesting that the well-known anticancer activity of celecoxib is not due to the inhibition of COX-2, but possibly is due to the inhibition of PDK1. It is highly desirable to develop new celecoxib derivatives as PDK1-specifc inhibitors to avoid the side effects of COX-2 inhibitors. To understand how PDK1 binds with celecoxib and its derivatives, we have performed extensive molecular docking and combined molecular dynamics (MD) simulations and molecular mechanics/Poisson-Boltzmann surface area (MM-PBSA) binding free energy calculations on eight representative PDK1 inhibitors, leading to the finding of a new, more favorable binding mode which is remarkably different from the previously proposed binding mode. Based on the determined most stable binding structures, the calculated binding free energies are all in good agreement with the corresponding experimental data, and the biological activity data available for celecoxib and its derivatives can be better interpreted. The obtained new insights, concerning both the binding mode and computational protocol, will be valuable not only for future rational design of novel, more potent PDK1-specific inhibitors as promising anticancer therapeutics, but also for rational design of drugs targeting other proteins.     

A remark on a theorem of Bavula on Lüroth extensions

Using a theorem of Roquette-Ohm [P. Roquette, Isomorphisms of generic splitting fields of simple algebras, J. Reine Angew. Math. 214-215 (1964) 207-226 and J. Ohm, On subfields of rational function fields, Arch. Math. 42 (1984) 136-138], we indicate a short proof that a rational extension of a Lüroth extension of a field k is a Lüroth extension of k. This assertion was proved by Bavula [V. Bavula, Lüroth field extensions, J. Pure Appl. Algebra 199 (2005) 1-10] with the added hypothesis that .     

3D refractive index profile for the characterization of necking phenomenon along stretched polypropylene fibres

The phenomenon of neck formation in polymers has attracted considerable attention. During the cold-drawing process an initial undrawn material is transformed into anisotropic one across a narrow transition region called ‘neck’. The Video Opto-Mechanical (VOM) device attached with multiple-beam Fizeau fringes techniques are used to stretch polypropylene (PP) fibres. A iPP sample is stretched to have a neck at room temperature. The optical properties of the deformed material over the necking region are examined. Another PP sample is stretched (without necking deformation) at room temperature and the optical properties are also examined. The task of this study is to characterize and assess the necking phenomenon along cold-drawn polypropylene (iPP) fibre axis. The effect of necking on the optical properties of the fibre is confirmed by the determination of the 3D refractive index profile at different regions along the deformed PP fibre. Also the orientation function is calculated for the necked sample. The contour lines of microinterferograms are given for illustrations.     

Synthesis and X-ray structure of neutral Pd(IV) hydride complexes supported by β-ketoimine ligands

A series of neutral palladium(IV) hydride complexes supported by β-ketoimine ligands was synthesized. Reaction of dichlorobis(acetonitrile)palladium(II) with β-ketoamines (1–4) in dichloromethane at room temperature generated dark red solids of [PdCl₂(β-ketoimine)(H)] (6–9) in which the central carbon of the ketoimine ligand is σ-bound to the palladium. All the new complexes have been characterized by NMR and IR spectroscopy. The structure of complex(9) has been solved by X-ray crystallography.     

Adsorption Properties of Uranium (VI) Ions on Reactive Crosslinked Acrylamidoxime and Acrylic Acid Copolymer Resins

Crosslinked acrylic acid (AA) acrylonitrile (AN) copolymer was prepared by suspension copolymerization in the presence of poly (vinyl alcohol) as suspending agent and N,N-methylenebisacrylamide (MBA) and divinylbenzene (DVB) as crosslinking agents. The molecular ratios between AN and AA was 95: 5 mol%. Different ratios 2, 5, and 10 wt% of crosslinkers was used. The nitrile group of the copolymer was converted to acrylamidoxime in the presence of hydroxylamine. Morphologies of the prepared resins were examined by scanning electron microscope (SEM). Recovery of uranium ions was investigated. The adsorption of uranium was occurred in nitric acid, hydrochloric acid and sulfuric acid solutions. Effect of pH, time of loading, type of acid, ratio, and type of crosslinker were investigated. Regeneration of eluted resins was determined.     

Solid-phase intermolecular radical reactions 2: synthesis of C-glycopeptide mimetics via a novel acrylate acceptor

[reaction: see text] A novel tetrafluorophenol-linked acrylate is reported as an activated acceptor for intermolecular radical reactions. Addition of alkyl radicals led to pure products in good yields. We include here the first syntheses of C1- and C6-linked glycosides using a solid-phase radical methodology.     

Effect of Methacrylated Hyperbranched Polymers on the Fracture Properties of Denture Base Materials

Hyperbranched polymers have the potential to reinforce crosslinked polymeric materials. In this study several concentrations of a methacrylated hyperbranched polyether are formulated with a denture base resin and cured. The denture base resin is a polymethyl methacrylate based resin. The fracture toughness of each of these concentrations was measured and compared to control. Only the 1% concentration had a significantly higher fracture toughness compared to the control. This is similar to other results that are found in the literature.     

Sustainable Production of Synthesis Gases via State of the Art Metal Supported Catalytic Systems: An Overview

Dry reforming of methane (CH₄) with carbon dioxide (CO₂) catalysts produces synthesis gas at atmospheric pressure. Synthesis gas is important feed stock to chemical and petrochemical industries to produce chemicals such as methanol and ammonia. It is also a source of hydrogen that is potential to fuel cells. Reforming reactions have also environmental benefit as CO₂ and CH₄, which are classified as green house gases, that cause global warming, are consumed. Reforming with CO₂ is attractive method since it can be employed in areas where water is not available. Considerable efforts have been made to obtain catalysts for dry reforming to achieve both high activity and good stability. In this review, we will take an over view of the dry reforming process and concentrate on the various catalysts used in the process, in general and Ni/Al₂O₃ catalytic system in particular and report the available data in the literature and the present state of the art for this process.     

Synthesis of New Phosphonate Derivatives of Naphtho[2,1-b[Pyran]3,2-e][1,2,4]Triazolo [1,5-c]Pyrimidines

Abstract

The synthesis of new naphthopyranotriazolopyrimidines phosphonates 4a–i in good yields (74%–93%) has been accomplished via Michaelis–Arbusov rearrangement by the reaction of trialkyl phosphite with naphthopyranotriazolopyrimidines chloride 3a–e, which were obtained from α-functionalized iminoethers 1 in two steps. The synthesized compounds 4a–i were completely characterized by IR, ¹H, ¹³C, and ³¹P NMR and HRMS.

Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.     

Chitosan and Lecithin Ameliorate Osteoarthritis Symptoms Induced by Monoiodoacetate in a Rat Model

The present work aimed to assess the chondroprotective influence of chitosan and lecithin in a monoiodoacetate (MIA)-induced experimental osteoarthritis (OA) model. Forty male rats weighing 180–200 g were randomly distributed among the following five experimental groups (eight per group): control, MIA-induced OA, MIA-induced OA + chitosan, MIA-induced OA + lecithin, and MIA-induced OA + chitosan + lecithin. The levels of TNF-α, IL6, RF, ROS, and CRP, as well as mitochondrial markers such as mitochondrial swelling, cytochrome C oxidase (complex IV), MMP, and serum oxidative/antioxidant status (MDA level) (MPO and XO activities) were elevated in MIA-induced OA. Also, SDH (complex II) activity in addition to the levels of ATP, glutathione (GSH), and thiol was markedly diminished in the MIA-induced OA group compared to in control rats. These findings show that mitochondrial function is associated with OA pathophysiology and suggest that chitosan and lecithin could be promising potential ameliorative agents in OA animal models. Lecithin was more effective than chitosan in ameliorating all of the abovementioned parameters.