Hot-spot guided design of macrocyclic inhibitors of the LSD1-CoREST1 interaction

New modalities such as cyclic peptides are attractive structures to inhibit challenging targets. The interaction between LSD1 and CoREST1 is required for histone demethylation and represents an attractive therapeutic target. The large interaction surface between these two proteins was analyzed by virtual alanine scanning using DrugScore PPI and a cluster of hot-spot residues was identified on CoREST1. The cluster was converted into a series of cyclic peptides and the inhibitory potency was optimized by stereochemical inversion at one of the amino acids alpha carbons combined with modification of amino acid side chains. Active peptides were further studied by variable temperature ¹H NMR and docking to evaluate the effect of conformation on binding. Potent inhibitors of the challenging PPI were obtained and will allow future optimization into more druglike structures.     

Crystal and molecular structure of benzoaza-12-crown-4 hydrochloride

Journal of Structural Chemistry - The X-ray crystallographic analysis of benzoaza-12-crown-4 hydrochloride crystals is performed for the first time: space group P1, a = 7.7497(4) Å, b =...     

Approximate elongation flow properties utilising the opposed orifice technique – Correction for shear and inertia

Mackay et al. (1995) have presented an approximate technique to determine the elongation viscosity from pressure drop measurements in a simple stagnation flow device. In the present paper we describe experiments using a high viscosity Newtonian oil, aimed at probing some of the assumptions made by Mackay et al. We find that Trouton ratios calculated using the original analysis are well above the value of three expected for Newtonian fluids. Finite element simulations of the flow field show this is due to the net pressure drop having a substantial shear contribution, which should be corrected for before the Trouton ratios are evaluated. Interestingly, most of the shear correction is due to shear on the inside of the orifice near the exit from the central flow region. The shear contribution to the pressure drop occurs for all flow rates, however, at large flow rates there is also an inertial correction to the pressure drop. In this paper we describe an approximate method that corrects for both shear and inertial effects. With these effects recognised and corrected for, the measured Trouton ratios are reduced to around three. Received: 15 December 1997 Accepted: 16 March 1998     

Large area laser surface micro/nanopatterning by contact microsphere lens arrays

Laser surface micro/nanopatterning by particle lens arrays is a well-known technique. Enhanced optical fields can be achieved on a substrate when a laser beam passes through a self-assembled monolayer of silica microspheres placed on the substrate. This enhanced optical field is responsible for ablative material removal from the substrate resulting in a patterned surface. Because of the laser ablation, the microspheres are often ejected from the substrate during laser irradiation. This is a major issue impeding this technique to be used for large area texturing. We explored the possibility to retain the spheres on the substrate surface during laser irradiation. A picosecond laser system (wavelength of 515 nm, pulse duration 6.7 ps, repetition rate 400 kHz) was employed to write patterns through the lens array on a silicon substrate. In this experimental study, the pulse energy was found to be a key factor to realize surface patterning and retain the spheres during the process. When the laser pulse energy is set within the process window, the microspheres stay on the substrate during and after laser irradiation. Periodic patterns of nanoholes can be textured on the substrate surface. The spacing between the nanoholes is determined by the diameter of the microspheres. The depth of the nanoholes varies, depending on the number of laser pulses applied and pulse energy. Large area texturing can be made using overlapping pulses obtained through laser beam scanning.     

Parallel nanostructuring of GeSbTe film with particle mask

Parallel nanostructuring of a GeSbTe film may significantly improve the recording performance in data storage. In this paper, a method that permits direct and massively parallel nanopatterning of the substrate surface by laser irradiation is investigated. Polystyrene spherical particles were deposited on the surface in a monolayer array by self-assembly. The array was then irradiated with a 248-nm KrF laser. A sub-micron nanodent array can be obtained after single-pulse irradiation. These nanodents change their shapes at different laser energies. The optical near-field distribution around the particles was calculated according to the exact solution of the light-scattering problem. The influence of the presence of the substrate on the optical near field was also studied. The mechanisms for the generation of the nanodent structures are discussed. PACS 81.16.Mk; 61.80.Ba; 81.16.Rf; 81.65.Cf     

Optical properties of BiB3O6 with different phase matching orientations

Basic optical properties of the new nonlinear crystal BiB₃O₆ (BIBO) are measured for second harmonic generation (SHG) of 1064 nm radiation. These properties include the effective nonlinearities for different phase matching orientations, the corresponding acceptance bandwidths and the optical losses. Effective nonlinearities of up to 3.2 pm/V (ϕ=90°, θ=-11°) and losses of less than 0.1 %/cm at 1064 nm indicate that BIBO is a promising new nonlinear crystal for SHG of 1064 nm radiation. A two-dimensional measurement with high spatial resolution of the SHG efficiency and the optical homogeneity, clearly demonstrate the high optical quality of BIBO crystals now available. PACS 42.65.Ky; 42.70.Mp     

Sodium dodecyl sulfate—polyethyleneimine—water system. Self-organization and catalytic activity

Concentration boundaries within which polymer—colloid structures exist in a sodium dodecyl sulfate—polyethyleneimine—water system were determined. The catalytic effect of this composition was found for the hydrolysis of phosphonic acid esters. The found acceleration of hydrolysis up to 25-fold is caused by reagent concentrating in a catalytic complex.__________Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 630–638, March, 2005.     

Dinuclear rhodium(II) pivalate complexes with N-donor ligands

Eight dinuclear rhodium(II) complexes containing various, (primarily, polyfunctional) N-donor ligands in the trans position with respect to the Rh-Rh bond were synthesized and characterized by X-ray diffraction. In the Chinese-lantern dinuclear rhodium(II) pivalates, Rh^II ₂ (μ-OOCCMe₃)₄(L)₂ (L is 2,3-diaminopyridine (2), 7,8-benzoquinoline (4), 2,2′:6′,2″-terpyridine (5), N-phenyl-o-phenylenediamine (7)), and Rh^II ₂ (μ-OOCCMe₃)₄L¹L² (3, L¹ is 2-phenylpyridine, L² = MeCN), the steric effects of the axial ligands are most strongly reflected in the Rh-N(L) and Rh-Rh bond lengths. The introduction of chelating ligands containing a conformationally rigid chelate ring leads to the cleavage of two carboxylate bridges to form the dinuclear double-bridged structure Rh^II ₂ (μ- OOCCMe₃)₂(OCCMe₃)₂(η²-L³)₂, where L³ is 8-amino-2,4-dimethylquinoline (6). The reaction of complex 7 containing coordinated N-phenyl-o-phenylenediamine with pyrrole-2,5-dialdehyde afforded the new Rh^II ₂(μ-OOCCMe₃)₄(L⁴)₂ complex (8) containing 5-(1-phenyl-1-H-benzimidazol-2-yl)-1H-pyrrole-2-carbaldehyde (L⁴) in the axial positions of the dirhodium tetracarboxylate fragment. The coordinated diamine differs in reactivity from the free diamine. The reaction of the former with the above dialdehyde affords the [1+1]-condensation product, viz., 5-{(E)-[(2-anilinophenyl)imino]methyl}-1-H-pyrrole-2-carbaldehyde, whereas the reaction of unsubstituted o-phenylenediamine gives 5-{(E)-[(2-aminophenyl)imino]methyl}-1-H-pyrrole-2-carbaldehyde (L⁵) . The reaction of the latter with Rh^II ₂(μ-OOCCMe₃)₄(H₂O)₂ affords the dinuclear complex Rh^II ₂(μ-OOCCMe₃)₂(OOCCMe₃)₂(η²-L⁵)₂ (9), which is an analog of complex 6 containing only two bridging carboxylate groups.__________Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 581–591, March, 2005.     

Sterilization by Low-Pressure Plasma: The Role of Vacuum-Ultraviolet Radiation

Low-pressure plasma is a promising method for destroying microorganisms, an alternative to conventional methods, which have numerous drawbacks. Several plasma-based sterilization technologies are presently under development, even though the exact role of the various plasma constituents, for example ultraviolet radiation, on the sterilization mechanism is still unknown and subject to controversy. In this study, we first report high sporicidal activity of a microwave (MW) plasma compared to its radio-frequency (RF) counterpart, which we believe to be due to the higher concentration of reactive particles in the former plasma. We then report a relatively low sporicidal efficacy of vacuum ultraviolet (VUV) radiation (between 115 and 170 nm) emitted by an hydrogen MW plasma, in spite of the high effectiveness of these photons to break chemical bonds. We discuss these results in terms of etching (ablation), which we have observed for both synthetic polymers and spores, and in terms of other possible mechanisms proposed in the literature. The sporicidal effectiveness of VUV/UV radiation appears to vary markedly with wavelength and intensity, on account of spore structure and molecular absorption.