Identification of Flavonoids as Putative ROS-1 Kinase Inhibitors Using Pharmacophore Modeling for NSCLC Therapeutics

Non-small cell lung cancer (NSCLC) is a lethal non-immunogenic malignancy and proto-oncogene ROS-1 tyrosine kinase is one of its clinically relevant oncogenic markers. The ROS-1 inhibitor, crizotinib, demonstrated resistance due to the Gly2032Arg mutation. To curtail this resistance, researchers developed lorlatinib against the mutated kinase. In the present study, a receptor-ligand pharmacophore model exploiting the key features of lorlatinib binding with ROS-1 was exploited to identify inhibitors against the wild-type (WT) and the mutant (MT) kinase domain. The developed model was utilized to virtually screen the TimTec flavonoids database and the retrieved drug-like hits were subjected for docking with the WT and MT ROS-1 kinase. A total of 10 flavonoids displayed higher docking scores than lorlatinib. Subsequent molecular dynamics simulations of the acquired flavonoids with WT and MT ROS-1 revealed no steric clashes with the Arg2032 (MT ROS-1). The binding free energy calculations computed via molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) demonstrated one flavonoid (Hit) with better energy than lorlatinib in binding with WT and MT ROS-1. The Hit compound was observed to bind in the ROS-1 selectivity pocket comprised of residues from the β-3 sheet and DFG-motif. The identified Hit from this investigation could act as a potent WT and MT ROS-1 inhibitor.     

Imaging the In Vivo Degradation of Tissue Engineering Implants by Use of Supramolecular Radiopaque Biomaterials

For in situ tissue engineering (TE) applications it is important that implant degradation proceeds in concord with neo‐tissue formation to avoid graft failure. It will therefore be valuable to have an imaging contrast agent (CA) available that can report on the degrading implant. For this purpose, a biodegradable radiopaque biomaterial is presented, modularly composed of a bisurea chain‐extended polycaprolactone (PCL2000‐U4U) elastomer and a novel iodinated bisurea‐modified CA additive (I‐U4U). Supramolecular hydrogen bonding interactions between the components ensure their intimate mixing. Porous implant TE‐grafts are prepared by simply electrospinning a solution containing PCL2000‐U4U and I‐U4U. Rats receive an aortic interposition graft, either composed of only PCL2000‐U4U (control) or of PCL2000‐U4U and I‐U4U (test). The grafts are explanted for analysis at three time points over a 1‐month period. Computed tomography imaging of the test group implants prior to explantation shows a decrease in iodide volume and density over time. Explant analysis also indicates scaffold degradation. (Immuno)histochemistry shows comparable cellular contents and a similar neo‐tissue formation process for test and control group, demonstrating that the CA does not have apparent adverse effects. A supramolecular approach to create solid radiopaque biomaterials can therefore be used to noninvasively monitor the biodegradation of synthetic implants.     

Coupled tapering/uptapering of soliton pairs in nonlinear media

Phenomenon of coupled tapering/uptapring of two mutually incoherent beams coaxially co-propagating in a nonlinear medium with small gain or loss has been investigated in this paper using standard parabolic equation approach (PEA) and the results are compared with the results obtained by Beam Propagation Method (BPM), i.e., by direct simulations of the underlying Nonlinear Schrödinger Equation (NLSE). The PEA results are shown to be in excellent agreement with the BPM results. It is seen that both beams of the pair induce uptapering in each other in presence of losses and tapering in presence of gain. When the medium offers gain to the first beam and losses to the other, both beams taper. When the medium offers gain/absorption to only one of the two beams, the beam undergoes self-tapering/self-uptapering and induces a taperd/uptaperd waveguide. The other beam (for which the medium is lossless) uptapers/tapers due to the taperd/uptaperd waveguide created by the first beam.     

Quench dynamics of edge states in 2-D topological insulator ribbons

We study the dynamics of edge states of the two dimensional BHZ Hamiltonian in a ribbon geometry following a sudden quench to the quantum critical point separating the topological insulator phase from the trivial insulator phase. The effective edge state Hamiltonian is a collection of decoupled qubit-like two-level systems which get coupled to bulk states following the quench. We notice a pronounced collapse and revival of the Lochschmidt echo for low-energy edge states illustrating the oscillation of the state between the two edges. We also observe a similar collapse and revival in the spin Hall current carried by these edge states, leading to a persistence of its time-averaged value.     

Development and Validation of a High-Performance Thin-Layer Chromatographic Method for the Simultaneous Estimation of Torsemide and Eplerenone by Quality by Design Approach

JPC – Journal of Planar Chromatography – Modern TLC - This paper includes the development of a novel, systematic, quality by design (QbD)-based high-performance thin-layer...     

Interaction potentials and transport properties of coinage metal cations in rare gases

High-level ab initio calculations are performed on the coinage metal cations (Cu+, Ag+, and Au+) interacting with each of the rare gases [Rg (Rg=He to Rn)]. The RCCSD(T) procedure is employed, with basis sets being of approximately quintuple-zeta quality, but with the heavier species using relativistic effective core potentials. The interaction potentials are compared to experimental and theoretical data where they exist. In addition, transport coefficients for the mobility and diffusion of the cations in the rare gases are calculated. The latter have involved a rewriting of some of the programs used, and the required modifications are discussed. The mobility results indicate that, rather than being a rare occurrence, mobility minima may be common phenomena. Finally, a new estimate is put forward for the validity of zero-field mobilities in ion mobility spectrometry.     

Acceptor-substituted ferrocenium salts as strong, single-electron oxidants: synthesis, electrochemistry, theoretical investigations, and initial synthetic application

A series of mono- and 1,1'-diheteroatom-substituted ferrocene derivatives as well as acylated ferrocenes was prepared efficiently by a unified strategy that consists of selective mono- and 1,1'-dilithiation reactions and subsequent coupling with carbon, phosphorus, sulfur and halogen electrophiles. Chemical oxidation of the ferrocene derivatives by benzoquinone, 2,3-dichloro-5,6-dicyanobenzoquinone, AgPF(6) , or 2,2,6,6-tetramethyl-1-oxopiperidinium hexafluorophosphate provided the corresponding ferrocenium salts. The redox potentials of the synthesized ferrocenes were determined by cyclic voltammetry, and it was observed that all new ferrocenium salts have stronger oxidizing properties than standard ferrocenium hexafluorophosphate. An initial application of selected derivatives in an oxidative bicyclization revealed that they mediate the transformation under considerably milder conditions than ferrocenium hexafluorophosphate. Quantum chemical calculations of the reduction potentials of the substituted ferrocenium ions were carried out by using a standard thermodynamic cycle that involved the gas-phase energetics and solvation energies of the contributing species. A remarkable agreement between theory and experiment was found: the mean average deviation amounted to only 0.030?V and the maximum deviation to 0.1?V. This enabled the analysis of various physical contributions to the computed reduction potentials of these ferrocene derivatives, thereby providing insight into their electronic structure and physicochemical properties.     

QSAR based modeling of inhibitory activity of alkenyldiarylmethane derivatives

A series of alkenyldiarylmethanes (ADAMs) were subjected to QSAR analysis by using linear free energy relationship model of Hansch. QSAR has been developed using steric, electronic and topological parameters along with appropriate dummy variable. Statistical techniques were applied to identify the structural and physicochemical requirements for ADAMs. The results are critically discussed on the basis of regression data and cross-validation techniques.     

Acceptor‐Substituted Ferrocenium Salts as Strong,Single‐Electron Oxidants: Synthesis,Electrochemistry, Theoretical Investigations,and Initial Synthetic Application

A series of mono‐ and 1,1′‐diheteroatom‐substituted ferrocene derivatives as well as acylated ferrocenes was prepared efficiently by a unified strategy that consists of selective mono‐ and 1,1′‐dilithiation reactions and subsequent coupling with carbon, phosphorus, sulfur and halogen electrophiles. Chemical oxidation of the ferrocene derivatives by benzoquinone, 2,3‐dichloro‐5,6‐dicyanobenzoquinone, AgPF₆, or 2,2,6,6‐tetramethyl‐1‐oxopiperidinium hexafluorophosphate provided the corresponding ferrocenium salts. The redox potentials of the synthesized ferrocenes were determined by cyclic voltammetry, and it was observed that all new ferrocenium salts have stronger oxidizing properties than standard ferrocenium hexafluorophosphate. An initial application of selected derivatives in an oxidative bicyclization revealed that they mediate the transformation under considerably milder conditions than ferrocenium hexafluorophosphate. Quantum chemical calculations of the reduction potentials of the substituted ferrocenium ions were carried out by using a standard thermodynamic cycle that involved the gas‐phase energetics and solvation energies of the contributing species. A remarkable agreement between theory and experiment was found: the mean average deviation amounted to only 0.030 V and the maximum deviation to 0.1 V. This enabled the analysis of various physical contributions to the computed reduction potentials of these ferrocene derivatives, thereby providing insight into their electronic structure and physicochemical properties.