Mitochondria-targeted chemotherapeutics: the rational design of gold(I) N-heterocyclic carbene complexes that are selectively toxic to cancer cells and target protein selenols in preference to thiols

A family of lipophilic, cationic Au(I) complexes of N-heterocyclic carbenes (NHCs) have been designed as new mitochondria-targeted antitumor agents that combine both selective mitochondrial accumulation and selective thioredoxin reductase inhibition properties within a single molecule. Two-step ligand exchange reactions with cysteine (Cys) and selenocysteine (Sec) occur with release of the NHC ligands. At physiological pH the rate constants for the reactions with Sec are 20- to 80-fold higher than those with Cys. The complexes are selectively toxic to two highly tumorigenic breast cancer cell lines and not to normal breast cells, and the degree of selectivity and potency are optimized by modification of the substituent on the simple imidazolium salt precursor. The lead compound is shown to accumulate in mitochondria of cancer cells, to cause cell death through a mitochondrial apoptotic pathway and to inhibit the activity of thioredoxin reductase (TrxR) but not the closely related and Se-free enzyme glutathione reductase.     

$$L^1$$ penalization of volumetric dose objectives in optimal control of PDEs

This work is concerned with a class of PDE-constrained optimization problems that are motivated by an application in radiotherapy treatment planning. Here the primary design objective is to minimize the volume where a functional of the state violates a prescribed level, but prescribing these levels in the form of pointwise state constraints leads to infeasible problems. We therefore propose an alternative approach based on \(L^1\) penalization of the violation that is also applicable when state constraints are infeasible. We establish well-posedness of the corresponding optimal control problem, derive first-order optimality conditions, discuss convergence of minimizers as the penalty parameter tends to infinity, and present a semismooth Newton method for their efficient numerical solution. The performance of this method for a model problem is illustrated and contrasted with an alternative approach based on (regularized) state constraints.     

Using in situ Raman monitoring as a tool for rapid optimisation and scale-up of microwave-promoted organic synthesis: esterification as an example

Microwave-promoted esterification reactions have been monitored using in situ Raman spectroscopy. Having optimised a reaction on a 23 mmol scale, it was transferred to a larger reaction vessel and scaled up to 0.26 mol, again with Raman monitoring. With conditions in hand, an automated stop-flow apparatus was used to prepare 5.7 moles of product.     

A TEM and XRD study of the SbNbSe3 misfit layer structures

Two new misfit layer structures have been synthesized within the Sb-Nb-Se system. Powder X-ray diffraction and electron microscopy techniques (electron diffraction, HREM, XEDS) have been used to determine the nature of their structure. According to TEM and XEDS data (for more than 15 crystals studied) both phases are monolayer type, i.e. (SbSe)1+delta (NbSe2). Electron microscopy reveals a composite modulated structure that consists of the periodical intergrowth of a pseudotetragonal SbSe layer, denominated as Q, and a pseudohexagonal layer NbSe2, denominated as H. Both layers fit along b, stack along c and do not fit along a (misfit) giving rise to an incommensurate modulation along this direction. The two phases differ in the symmetry of the Q layers being in one case orthorhombic (for delta = 0.17) and monoclinic in the other (for delta = 0.19). After the characterization of the sample by electron microscopy the unit cells of the basic layers could be refined for both phases by powder X-ray diffraction: aQ = 5.824(2) A, bQ = 5.962(5) A, cQ = 23.927(6) A, alpha = 90 degrees, beta = 90 degrees and gamma = 90 degrees and aH = 3.415(5) A, bH = 5.962(6) A,, cH = 11.962(1) A, alpha = 90 degrees, beta = 90 degrees and gamma = 90 degrees for the orthorhombic phase; aQ = 5.844(2) A, bQ = 5.981(1) A, cQ = 23.919(5) A, alpha = 90 degrees, beta = 90 degrees and gamma = 96.00(3)degrees and aH = 3.439(1) A, bH = 5.994(2) A, cH = 11.956(3) A, alpha = 90 degrees, beta = 90 degrees and gamma = 90 degrees for the monoclinic phase. The phase with the monoclinic Q-sublattice often appears as twinned crystals. The more abundant crystals are disordered intergrowths of both monolayer phases.     

Ab initio modelling of boron and nitrogen in diamond nanowires

In this study an analysis is presented of the bonding and structural properties of dehydrogenated and hydrogenated doped cylindrical diamond nanowires calculated using the Vienna Ab Initio Simulation Package, employing density functional theory within the generalized-gradient approximation. The dopants studied here have been inserted substitutionally along the axis of an infinite one-dimensional diamond nanowire and include the single-electron acceptor boron and the single-electron donor nitrogen. The doped nanowires have then been re-relaxed, and properties compared with the undoped structures. The structural properties of relaxed nanowires considered here include an examination bonding via the electron charge density, with the aim of providing a better understanding of the effects of dopants on the stability of diamond nanostructures and nanodevices.     

Proton transfer in the hydrogen-bonded chains of lepidocrocite: a computational study

A responsible approach to the development of alternative energy sources, storage and conversion systems is to utilize abundant materials, with minimal or no negative environmental impacts. Here we report that lepidocrocite (γ-FeOOH, a naturally occurring metastable phase of iron oxyhydroxide) shows great promise as a proton conductor, based on sophisticated first-principles calculations that include the important corrections of on-site Coulomb interactions for this strongly correlated material. Our results show how proton transfer is facilitated by phonon vibration modes and relatively low transition energy barriers.     

Multimetal Fischer carbene complexes of Group VI transition metals: synthesis, structure and substituent effect investigation

Fischer carbene complexes of tungsten with substituents containing up to two additional different transition metals, with all the metals in electronic contact with the carbene carbon atom, were synthesised and studied both in solution and in the solid state. For the complexes of the type [W(CO)(5){C(OR')R}], the substituents chosen were heteroaromatic 2-benzo[b]thienyl (2-BT), or 2-BT π-bonded to a chromium tricarbonyl fragment ([Cr(CO)(3)(2-η(6)-BT)]) or ferrocenyl (Fc) as the R-substituent, while the OR'-substituent was systematically varied between an ethoxy or a titanoxy group, to yield the complexes 1b (R' = Et, R = 2-BT), 2b (R' = Et, R = [Cr(CO)(3)(2-η(6)-BT)]), 3b (R' = TiCp(2)Cl, R = 21-BT), 4b (R' = TiCp(2)Cl, R = [Cr(CO)(3)(2-η(6)-BT)]), 5b (R' = Et, R = Fc) and 6b (R' = TiCp(2)Cl, R = Fc). The structural features and their relevance to bonding in the multimetal carbene compounds of both these tungsten and the analogous chromium complexes were investigated as they represent indicators of possible reactivity sites in multimetal carbene assemblies. The possibility of using DFT calculations to quantify the effect of metal-containing substituents on the carbene ligands was tested and correlated with experimental parameters by employing methods such as vibrational spectroscopy, molecular orbital analysis, and cyclic voltammetry.     

State-Constrained Optimization of PDEs via Infinite Penalization Methods

We consider optimization problems constrained by partial differential equations (PDEs) with additional constraints placed on the solution of the PDEs. Specifically, we consider problems involving constraints on the average value of the state in subdomains. We develop a general framework using infinite-valued penalization functions and Clarke generalized gradients to obtain optimality conditions. A numerical example involving a linear elliptic PDE is presented. (© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim)     

Synthetic Retinoids: Structure–Activity Relationships

Retinoid signalling pathways are involved in numerous processes in cells, particularly those mediating differentiation and apoptosis. The endogenous ligands that bind to the retinoid receptors, namely all‐trans‐retinoic acid (ATRA) and 9‐cis‐retinoic acid, are prone to double‐bond isomerisation and to oxidation by metabolic enzymes, which can have significant and deleterious effects on their activities and selectivities. Many of these problems can be overcome through the use of synthetic retinoids, which are often much more stable, as well as being more active. Modification of their molecular structures can result in retinoids that act as antagonists, rather than agonists, or exhibit a large degree of selectivity for particular retinoid‐receptor isotypes. Several such selective retinoids are likely to be of value as pharmaceutical agents with reduced toxicities, particularly in cancer therapy, as reagents for controlling cell differentiation, and as tools for elucidating the precise roles that specific retinoid signalling pathways play within cells.     

Fast neutron scattering from cesium

A study was made of the(n, n), (n, n′) and (n, n′ γ) reactions which occur when a cesium scattering sample is exposed to mono-energetic neutrons of energies ranging from 120 to 1910 keV. Total cross sections, elastic scattering angular distributions and excitation functions for inelastic scattering were measured with a neutron time-of-flight spectrometer. Results are compared with statistical theory. A 40 cc Ge(Li) detector was used in the time gated mode to measure γ-rays from the (n, n′ γ) reaction. These data were used to refine and extend the energy level scheme derived from the neutron spectroscopy measurements and mainly confirm the results of recent, similar measurements.