Analysis of chemical shift changes reveals the binding modes of isoindolinone inhibitors of the MDM2-p53 interaction

In this study we present a method for defining the binding modes of a set of structurally related isoindolinone inhibitors of the MDM2-p53 interaction. This approach derives the location and orientation of isoindolinone binding, based on an analysis of the patterns of magnitude and direction of chemical shift perturbations for a series of inhibitors of the MDM2-p53 interaction. The MDM2-p53 complex is an attractive target for therapeutic intervention in cancer cells with intact tumor suppressor p53, as it offers the possibility of releasing p53 by blocking the MDM2-p53 binding site with a small molecule antagonist to promote apoptosis. Isoindolinones are a novel class of MDM2-antagonists of moderate affinity, which still require the development of more potent candidates for clinical applications. As the applicability of conventional structural methods to this system is limited by a number of fundamental factors, the exploitation of the information contained in chemical shift perturbations has offered a useful route to obtaining structural information to guide the development of more potent compounds. For a set of 12 structurally related isoindolinones, the data suggests 4 different orientations of binding, caused by subtle changes in the chemical structure of the inhibitors.     

Synthesis of poly(vinyl acetate)-b-poly(dimethylsiloxane)-b-poly(vinyl acetate) triblock copolymers by iodine transfer polymerization

Iodine transfer polymerization of vinyl acetate in bulk, initiated by α,α′-azobisisobutyronitrile at 80 °C, has been successfully performed in the presence of an α,ω-diiodo-poly(dimethylsiloxane) macrotransfer agent. The formation of a triblock copolymer PVAc-b-PDMS-b-PVAc has been proved by ¹H NMR and size exclusion chromatography analyses. The analysis of the chain-ends has been performed using ¹H NMR. It was found that a large amount of inverse chain-ends is present at the end of the polymerization. Moreover, the formation of several other side products by degradation of the functional chain-ends has been evidenced.     

Hexanuclear cobalt carbonyl carbide clusters: the interplay between octahedral and trigonal prismatic structures

The six-vertex cobalt carbonyl clusters [Co6C(CO)n](2-) (n = 12, 13, 14, 15, 16) with an interstitial carbon atom have been studied by density functional theory (DFT). These DFT studies indicate that the experimentally known structure of [Co6C(CO)15](2-) consisting of a Co6 trigonal prism with each of its edges bridged by carbonyl groups is a particularly stable structure lying more than 20 kcal/mol below any other [Co6C(CO)15](2-) structure. Addition of a CO group to this [Co6C(CO)15](2-) structure gives the lowest energy [Co6C(CO)16](2-) structure, also a Co6 trigonal prism with one of the vertical edges bridged by two CO groups and the remaining eight edges each bridged by a single CO group. However, this [Co6C(CO)16](2-) structure is thermodynamically unstable with respect to CO loss reverting to the stable trigonal prismatic [Co6C(CO)15](2-). This suggests that 15 carbonyl groups is the maximum that can be attached to a Co6C skeleton in a stable compound. The lowest energy structure of [Co6C(CO)14](2-) has a highly distorted octahedral Co6 skeleton and is thermodynamically unstable with respect to disproportionation to [Co6C(CO)15](2-) and [Co6C(CO)13](2-). The lowest energy [Co6C(CO)13](2-) structure is very similar to a known stable structure with an octahedral Co6 skeleton. The lowest energy [Co6C(CO)12](2-) structure is a relatively symmetrical D3d structure containing a carbon-centered Co6 puckered hexagon in the chair form.     

Mononuclear and binuclear rhenium carbonyl nitrosyls: comparison with their manganese analogues

The structures and energetics of Re(NO)(CO)n (n = 5, 4, 3, 2) and Re2(NO)2(CO)n (n = 7, 6) have been investigated using density functional theory. For Re(NO)(CO)4 the preferred structure is an equatorially substituted trigonal bipyramid analogous to the known structure of the manganese analogue. The lowest energy structures for the unsaturated Re(NO)(CO)n (n = 3, 2) species can be derived from this structure by removal of carbonyl groups. A structure is found for Re(NO)(CO)5 in which the NO ligand has attached to one of the CO ligands by forming a C-N bond to give an unprecedented eta(2)-OCNO ligand. However, this structure is predicted to undergo exothermic CO loss to give Re(NO)(CO)4. The preferred structures for the binuclear derivatives Re2(NO)2(CO)n (n = 7, 6) are structures unprecedented for the manganese analogues and consist of a Re(CO)5 unit linked to a Re(NO)2(CO)(n-5) unit. However, only slightly higher in energy are structures of the type Re2(mu-NO)2(CO)n with two bridging nitrosyl groups, similar to the global minima for the manganese analogues. These results predict extensive areas of new rhenium carbonyl nitrosyl chemistry. Thus the synthesis of Re(NO)(CO)4 by methods related to the synthesis of the manganese analogue appears to be feasible. In addition, the existence of an extensive series of Re(NO)2(CO)2X derivatives, as well as a Re2(NO)4(CO)4 dimer, is predicted.     

The Creutz-Taube complex revisited: DFT study of the infrared frequencies

The structural parameters, electronic properties, and infrared frequencies of three binuclear ruthenium complexes, [(NH(3))(5)Ru(pyrazine)Ru(NH(3))(5)](n+), n = 4-6, have been investigated with density functional theory. Structural analysis demonstrates that the structure of the mixed-valence 5+, or [II,III], is not an intermediate of the reduced 4+, or [II,II], and the oxidized 6+, or [III,III], compounds. Electronic structure comparison shows that the Ru d(yz) antibonding orbital is empty when n = 5 and 6 and occupied, when n = 4. The infrared frequencies have been calculated for a sequence of models with increasingly detailed accounts of counterions, ranging from the free Creutz-Taube 5+ ion, over jellium embedded, COnductor-like Screening MOdel (COSMO), to the experimental structure of the triclinic [II,III](tos)(5).4H(2)O (tos = p-toluenesulfonate) crystal. Analysis of the Ru vibrations shows that the spectra for the two symmetry-inequivalent Ru atoms are essentially the same. We find that Ru-Ru modes exist near three well-defined frequencies in the solid: at 145, 285, and 345 cm(-1). Similar results are also obtained for the simplified jellium and COSMO models. The spectral properties of these vibrational correlations testify to the existence of two coupled Ru atoms in the same charge state.     

Binuclear iron carbonyl nitrosyls: bridging nitrosyls versus bridging carbonyls

The iron carbonyl nitrosyls Fe 2(NO) 2(CO) n ( n = 7, 6, 5, 4, 3) have been studied by density functional theory (DFT) using the B3LYP and BP86 methods, for comparison of their predicted structures with those of isoelectronic cobalt carbonyl derivatives. The lowest energy structures for Fe 2(NO) 2(CO) 7 and Fe 2(NO) 2(CO) 6 have two NO bridges, and the lowest energy structure for Fe 2(NO) 2(CO) 5 has a single NO bridge with metal-metal distances (BP86) of 3.161, 2.598, and 2.426 A, respectively, corresponding to the formal metal-metal bond orders of zero, one, and two, respectively, required for the favored 18-electron configuration for the iron atoms. The heptacarbonyl Fe 2(NO) 2(CO) 7 is thermodynamically unstable with respect to CO loss to give Fe 2(NO) 2(CO) 6. The favored structures for the more highly unsaturated Fe 2(NO) 2(CO) 4 and Fe 2(NO) 2(CO) 3 also have bridging NO groups but avoid iron-iron bond orders higher than two by formal donation of five electrons from bridging NO groups with relatively short Fe-O distances. The lowest energy structures of the unsaturated Fe 2(NO) 2(CO) n derivatives ( n = 5, 4, 3) are significantly different from the isoelectronic cobalt carbonyls Co 2(CO) n +2 owing to the tendency for Fe 2(NO) 2(CO) n to form structures with bridging NO groups and metal-metal formal bond orders no higher than two.     

Optical response of the Cu2S2 diamond core in (NGuaS)2Cl2

Density functional theory (DFT) and time‐dependent DFT calculations are presented for the dicopper thiolate complex Cu₂(NGuaS)₂Cl₂ [NGuaS=2‐(1,1,3,3‐tetramethylguanidino) benzenethiolate] with a special focus on the bonding mechanism of the Cu₂S₂Cl₂ core and the spectroscopic response. This complex is relevant for the understanding of dicopper redox centers, for example, the Cu_A center. Its UV/Vis absorption is theoretically studied and found to be similar to other structural Cu_A models. The spectrum can be roughly divided in the known regions of metal d‐d absorptions and metal to ligand charge transfer regions. Nevertheless the chloride ions play an important role as electron donors, with the thiolate groups as electron acceptors. The bonding mechanism is dissected by means of charge decomposition analysis which reveals the large covalency of the Cu₂S₂ diamond core mediated between Cu and S‐S π and π* orbitals forming Cu‐S σ bonds. Measured resonant Raman spectra are shown for 360‐ and 720‐nm excitation wavelength and interpreted using the calculated vibrational eigenmodes and frequencies. The calculations help to rationalize the varying resonant behavior at different optical excitations. Especially the phenylene rings are only resonant for 720 nm. © 2016 Wiley Periodicals, Inc.     

Environmental noise – ‘Forgotten’ or ‘Ignored’ pollutant?

It has been 20 years since the European Commission adopted the Green Paper on Future Noise Policy in 1996, taking the first comprehensive step towards the development of an EU-wide noise policy. This document envisioned a directive that would harmonise methods for the assessment of environmental noise and the dissemination of information to the public. This led to the establishment of Directive 2002/49/EC in 2002 also known as the Environmental Noise Directive (END). The END called for the development of strategic noise maps and action plans across every EU Member State in five year intervals. Two phases of noise mapping and action planning have now been completed and Member States are about to embark on the third phase of noise mapping, due in 2017. Focussing on results reported to the European Commission, this study summarises the current state of noise mapping, 20 years after the publication of the Green Paper, and identifies critical needs for future noise mapping phases.     

The Linear KdV Equation with an Interface

The interface problem for the linear Korteweg–de Vries (KdV) equation in one-dimensional piecewise homogeneous domains is examined by constructing an explicit solution in each domain. The location of the interface is known and a number of compatibility conditions at the boundary are imposed. We provide an explicit characterization of sufficient interface conditions for the construction of a solution using Fokas’s Unified Transform Method. The problem and the method considered here extend that of earlier papers to problems with more than two spatial derivatives.