Synthesis and rotation barriers in 2, 6-Di-(o-anisyl) anisole

Variable temperature ¹H NMR spectroscopic studies of 2, 6-di(o-anisyl) anisole show syn and anti atropisomers at low temperature. The barrier for interconverting these isomers by rotation about the aryl-aryl bond, found by fitting the experimental data, is 41.2 kJ/mol

SYNTHESIS OF MODELS FOR NEIGHBORING PROLINE AMIDE AND ARYL PARTICIPATION IN ELECTRON TRANSFER FROM THIOETHERS

A series of 6-endo-(methylthio)-bicyclo[2.2.1]heptane-2-endo-proline amides was synthesized to study the neighboring proline amide participation in electron transfer from thioethers. The thioether with endo-pyrrolidine amide formed a two-center three-electron SO bond after one electron oxidation and the oxidation potential of the thioether was lowered by 530 mV and 330 mV compared to the corresponding exo-pyrrolidine amide and the primary amide analogues, respectively. The thioether with a proline methyl ester showed the oxidation potential of 410 mV higher than that of the pyrrolidine amide. The basis for this surprising result was revealed by an X-ray crystallographic structure study of the diastereomerically pure proline methyl ester which showed amide carbonyl n → methyl ester π* interaction which removes electron density from the neighboring amide which results in less effective neighboring amide participation in thioether oxidation. This accounts for the electrochemical result. A potent synthetic route for S-tert-butyl m-terphenyl thioethers was developed and a series of such thioethers was synthesized. Electrochemical studies showed through-space S∙∙∙π interaction with lower oxidation potentials for thioethers with more electron rich aromatic groups and higher oxidation potentials with electron withdrawing aromatic groups. Selective Suzuki reactions were discovered in which mono-coupling of the precursor dibromides could be achieved. A second coupling was then possible in which two different aromatic rings are attached to the central aryl thioether ring. This enabled the synthesis of a two-sulfur three-aromatic ring extended m-terphenyl thioether as a potential electron conductor. In support of this possibility this compound showed an oxidation potential of +0.99 V which is less positive than the +1.09 V measured for the mono-sulfur analog.Embargo: Release after 12/02/201

Spectroscopic Evidence for Through-Space Arene–Sulfur–Arene Bonding Interaction in <i>m</i>‑Terphenyl Thioether Radical Cations

Electronic absorption spectra and quantum chemical calculations of the radical cations of <i>m</i>-terphenyl <i>tert</i>-butyl thioethers, where the S–<i>t</i>-Bu bond is forced to be perpendicular to the central phenyl ring, show the occurrence of through-space [π···S···π]⁺ bonding interactions which lead to a stabilization of the thioether radical cations. In the corresponding methyl derivatives there is a competition between delocalization of the hole that is centered on a p-AO of the S atom into the π-system of the central phenyl ring or through space into the flanking phenyl groups, which leads to a mixture of planar and perpendicular conformations in the radical cation. Adding a second <i>m</i>-terphenyl <i>tert</i>-butyl thioether moiety does not lead to further delocalization; the spin and charge remain in one of the two halves of the radical cation. These findings have interesting implications with regard to the role of methionines as hopping stations in electron transfer through proteins

ARL-17477 is a dual inhibitor of NOS1 and the autophagic-lysosomal system that prevents tumor growth in vitro and in vivo

Abstract ARL-17477 is a selective neuronal nitric oxide synthase (NOS1) inhibitor that has been used in many preclinical studies since its initial discovery in the 1990s. In the present study, we demonstrate that ARL-17477 exhibits a NOS1-independent pharmacological activity that involves inhibition of the autophagy-lysosomal system and prevents cancer growth in vitro and in vivo. Initially, we screened a chemical compound library for potential anticancer agents, and identified ARL-17477 with micromolar anticancer activity against a wide spectrum of cancers, preferentially affecting cancer stem-like cells and KRAS-mutant cancer cells. Interestingly, ARL-17477 also affected NOS1-knockout cells, suggesting the existence of a NOS1-independent anticancer mechanism. Analysis of cell signals and death markers revealed that LC3B-II, p62, and GABARAP-II protein levels were significantly increased by ARL-17477. Furthermore, ARL-17477 had a chemical structure similar to that of chloroquine, suggesting the inhibition of autophagic flux at the level of lysosomal fusion as an underlying anticancer mechanism. Consistently, ARL-17477 induced lysosomal membrane permeabilization, impaired protein aggregate clearance, and activated transcription factor EB and lysosomal biogenesis. Furthermore, in vivo ARL-17477 inhibited the tumor growth of KRAS-mutant cancer. Thus, ARL-17477 is a dual inhibitor of NOS1 and the autophagy-lysosomal system that could potentially be used as a cancer therapeutic

Intramolecular Electron Transfer in Bipyridinium Disulfides

Reductive cleavage of disulfide bonds is an important step in many biological and chemical processes. Whether cleavage occurs stepwise or concertedly with electron transfer is of interest. Also of interest is whether the disulfide bond is reduced directly by intermolecular electron transfer from an external reducing agent or mediated intramolecularly by internal electron transfer from another redox-active moiety elsewhere within the molecule. The electrochemical reductions of 4,4′-bipyridyl-3,3′-disulfide (<b>1</b>) and the di-<i>N</i>-methylated derivative (<b>2</b>^<b>2+</b>) have been studied in acetonitrile. Simulations of the cyclic voltammograms in combination with DFT (density functional theory) computations provide a consistent model of the reductive processes. Compound <b>1</b> undergoes reduction directly at the disulfide moiety with a substantially more negative potential for the first electron than for the second electron, resulting in an overall two-electron reduction and rapid cleavage of the S–S bond to form the dithiolate. In contrast, compound <b>2</b>^<b>2+</b> is reduced at less negative potential than <b>1</b> and at the dimethyl bipyridinium moiety rather than at the disulfide moiety. Most interesting, the second reduction of the bipyridinium moiety results in a fast and reversible intramolecular two-electron transfer to reduce the disulfide moiety and form the dithiolate. Thus, the redox-active bipyridinium moiety provides a low energy pathway for reductive cleavage of the S–S bond that avoids the highly negative potential for the first direct electron reduction. Following the intramolecular two-electron transfer and cleavage of the S–S bond the bipyridinium undergoes two additional reversible reductions at more negative potentials

Neighboring π‑Amide Participation in Thioether Oxidation: Conformational Control

The electrochemical oxidation of thioethers is shown to be facilitated by neighboring amide participation. ¹H NMR spectroscopic analysis in acetonitrile solution of two conformationally constrained compounds with such facilitation shows that two-electron participation by the amide π₂ orbital can occur to stabilize the developing sulfur radical cation

Lumbar Fusion including Sacroiliac Joint Fixation Increases the Stress and Angular Motion at the Hip Joint: A Finite Element Study

Introduction: Adult spinal fusion surgery improves lumbar alignment and patient satisfaction. Adult spinal deformity surgery improves saggital balance not only lumbar lesion, but also at hip joint coverage. It was expected that hip joint coverage rate was improved and joint stress decreased. However, it was reported that adjacent joint disease at hip joint was induced by adult spinal fusion surgery including sacroiliac joint fixation on an X-ray study. The mechanism is still unclear. We aimed to investigate the association between lumbosacral fusion including sacroiliac joint fixation and contact stress of the hip joint. Methods: A 40-year-old woman with intact lumbar vertebrae underwent computed tomography. A three-dimensional nonlinear finite element model was constructed from the L4 vertebra to the femoral bone with triangular shell elements (thickness, 2 mm; size, 3 mm) for the cortical bone's outer surface and 2-mm (lumbar spine) or 3-mm (femoral bone) tetrahedral solid elements for the remaining bone. We constructed the following four models: a non-fusion model (NF), a L4-5 fusion model (L5F), a L4-S1 fusion model (S1F), and a L4-S2 alar iliac screw fixation model (S2F). A compressive load of 400 N was applied vertically to the L4 vertebra and a 10-Nm bending moment was additionally applied to the L4 vertebra to stimulate flexion, extension, left lateral bending, and axial rotation. Each model's hip joint's von Mises stress and angular motion were analyzed. Results: The hip joint's angular motion in NF, L5F, S1F, and S2F gradually increased; the S2F model presented the greatest angular motion. Conclusions: The average and maximum contact stress of the hip joint was the highest in the S2F model. Thus, lumbosacral fusion surgery with sacroiliac joint fixation placed added stress on the hip joint. We propose that this was a consequence of adjacent joint spinopelvic fixation. Lumbar-to-pelvic fixation increases the angular motion and stress at the hip joint