Hydroxamic Acids as PARP-1 Inhibitors: Molecular Design and Anticancer Activity of Novel Phenanthridinones

Poly(ADP-ribose)polymerase-1 (PARP-1) is a promising target for antitumor agents. This study presents the first evidence of hydroxamic acids as efficient PARP inhibitors. Molecular docking and molecular dynamics simulations revealed that N−O substituted phenanthridinones form a complex interplay with PARP-1. A series of cyclic aryl hydroxamic acids, N-(benzyloxy)- and N-(hydroxy)phenanthridinones, were prepared through a ligand-free methodology from N-(benzyloxy)benzamides using dual C−H/N−H bond activation. Three of the computed hit compounds exhibited significant activity in cell-based and enzymatic assays, inhibiting PARP-1 in the low-nanomolar range. The antiproliferative activity of all prepared compounds and the reference compounds PJ34 and Olaparib was evaluated in cancer cells (HepG2, BxPC3, MDA-MD-231, and HeLa) and in noncancer cell lines (NIH 3T3 and HEK 293). An N-(benzyloxy)- and an N-(hydroxy)phenanthridinone showed the most promising properties as leads for developing therapeutics with a submicromolar activity window. The study highlights the potential utility of this scaffold for PARP inhibitors and the importance of target-specific design to minimize toxicity and side effects.     

The Riemann-Lebesgue property is equivalent to the complete continuity property

It is known that every space with the complete continuity propertyalso has the Riemann–Lebesgue property. It turns out thatthe converse implication is also valid.     

Carbenoxolone does not cross the blood brain barrier: an HPLC study

Background  

Carbenoxolone (CBX) is a widely used gap junctional blocker. Considering several reports indicating that transient gap junctional blockade could be a favourable intervention following injuries to central nervous tissue, and some current enthusiasm in studies using systemic injections of CBX, it is imperative to consider the penetration of CBX into central nervous tissue after systemic administrations. So far, only very indirect evidence suggests that CBX penetrates into the central nervous system after systemic administrations. We thus determined the amounts of CBX present in the blood and the cerebrospinal fluid of rats after intraperitoneal administration, using high performance liquid chromatography     

Deformed gap space using macro-micro FEA model and transferred into a CFD model

Using a cylindrical nozzle and seat of a Pressure Relief Valve (PRV) the surface form and waviness is modelled using actual metrological data i. e. average surface form and waviness (W_a and W_sm) in a symmetry manner. To model the surface waviness the technique used is based on the summing technique created by Tsukizoe & Hisakado [1, 2] for micro contact analysis. Due to the actual surface form measurements being in the micro-meter range, the model is required to incorporate micro and macro-meter dimensions. The material in question is stainless steel. The deformed finite element analysis model is then transferred into a CAD geometry allowing the void space to be meshed and solved using computational fluid dynamics. © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim)     

Cyclic yield strength in definition of design limits for fatigue and creep

This study proposes a cyclic yield strength (CYS, σ^c_y) as a key characteristic for the definition of safe design for engineering structures operating under fatigue and creep conditions. CYS is defined on a cyclic stress-strain curve, while monotonic yield strength (MYS, σ^m_y) is defined on a monotonic stress-strain curve. Both values of σ^c_y and σ^m_y are identified using a 2-steps fitting procedure of the experimental stress-strain curves using Ramberg-Osgood and Chaboche material models. Comparison of σ^c_y and fatigue endurance limit σ^f_lim on the S-N fatigue curve reveals that they are approximately equal. Hence, basically safe fatigue design is guaranteed in purely elastic domain defined by the σ^c_y. A typical creep rupture curve in time-to-failure approach for creep analysis has 2 inflections corresponding to the σ^c_y and σ^m_y. These stresses separate 3 sections on the creep rupture curve, which are characterised by 3 different creep fracture modes and 3 creep deformation mechanisms. Thus, basically safe creep design is guaranteed in linear creep domain with brittle failure mode defined by the σ^c_y. These assumptions are confirmed for several structural low- and high-alloy steels for normal and high-temperature applications. (© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim)     

Light transmission in inhomogeneous birefringent medium as a function of propagation and observation angles

We use the Mueller matrix for inhomogeneous linear birefringent media derived in Savenkov et al. [Mueller-matrix model of an inhomogeneous linear birefringent medium: single scattering case. JQSRT 2007;106:475–86] to generate new results on the forward scattering of light using Cloude's coherence matrix method. We show that the intensity of scattered light (m₁₁) as a function of observation angle depends on the difference between refractive indices along the eigen polarizations resulting in intensity lost when unpolarized light propagates parallel to the optical axes compared to propagation orthogonal to the optical axis. For a given inhomogeneity (roughness), depolarization strongly depends on the direction of light propagation in the medium. The depolarization at 90° propagation angle is minimal for any value of inhomogeneity. Sample calculations are based on calcite.     

How many conformers determine the thymidine low-temperature matrix infrared spectrum? DFT and MP2 quantum chemical study

A comprehensive conformational analysis of isolated 2'-beta-deoxy-thymidine (T), canonical DNA nucleoside, has been performed by means of ab initio calculations at the MP2/6-311++G(d,p)//DFT B3LYP/6-31G(d,p) level of theory. At 298.15 K, all 92 conformers of isolated dT are within a 7.49 kcal/mol Gibbs energy range. Syn orientation for the base and South (S) conformers for the sugar dominate at this temperature: syn/anti = 61.6%:38.4% and S/N = 74.5%:25.5%. However, at 420 K, the majority of conformers contain anti base and the population of North (N) sugars increases: syn/anti = 38.0%:62.0% and S/N = 59.5%:40.5%. The whole conformational parameters (P, chi, gamma, delta, beta, epsilon, nu max) were analyzed as well as the energies of the OH...O intramolecular H-bonds on the basis of nu(OH) stretching vibrations. Convolution of calculated IR spectra of all of the T conformers appears consistent with its low-temperature matrix spectrum (Ivanov et al. Low Temp. Phys. 2003, 29, 809). The maximal discrepancy in frequencies between calculated and experimental spectra is less than 1%. A conclusion was made that for reliable reconstruction of the isolated nucleoside IR spectrum the quasi whole set of conformers should be taken into consideration. In essence, this result opens up a possibility to reconstruct IR spectra of isolated nucleosides at physiological temperatures with rather satisfactory probability.     

Polymer blends filled with carbon black: structure and electrical properties

Morphology and electrical conductivity of polymer blends based on polypropylene, polyethylene, polyoxymethylene, polyamide 12, co‐polymer ABS filled with carbon black (CB) were studied. When filler is introduced in polymer blend, three cases of filler spatial distribution can be obtained. CB can be distributed randomly within polymer matrix, can be situated in one of the polymer components or can be localized on the boundary of the polymer components. The existence of different cases of filled blends structure is defined by following reasons: thermodynamic factors (relationship between interface surface tensions of polymer‐filler γ_pf and polymer‐polymer surface tension γ_pp); kinetic factors (relationship between viscosities of polymer components); processing factors (methods of the filler introduction in the complex polymer matrix, which can enhance or depress the influence of thermodynamic and kinetic factors).