Palladium-catalyzed C-H dimethylamination of 1-chloromethyl naphthalenes with N,N-dimethylformamide as the dimethyl amino source.

Palladium-catalyzed remote C-H dimethylamination of 1-chloromethylnaphthalenes using N,N-dimethylformamide as the dimethylamino source is described for the first time. The dimethylamination took place exclusively at the 4-position of 1-chloromethylnaphthalenes in 2-methyltetrahydrofuran under mild conditions to afford 1-(N,N-dimethylamino)-4-alkylnaphthalenes in good to high yields. The halogen atom remained intact during the dimethylamination of 1-chloromethylnaphthalenes. A P,N bidentate ligand was conveniently synthesized and successfully utilized as the ligand in the Kumada-Corriu reaction.

One-pot synthesis of multisubstituted propenylbenzenes from benzyl chlorides through relay catalysis of palladium.

A strategy for the synthesis of multisubstituted propenylbenzenes using benzyl chlorides as starting materials is described. The palladium-catalyzed allylative dearomatization and the subsequent Wagner-Meerwein rearrangement as well as the olefin isomerization proceeded smoothly under mild conditions to produce propenylation products in good yields with high regioselectivity. Control experiments and cyclic voltammetry analysis suggest that Bu3SnCl, a by-product generated in the first step of allylative dearomatization, plays an essential role in the third step of olefin isomerization in the presence of a Brønsted acid.

A step-by-step approach for assessing acute oral toxicity without animal testing for additives of quasi-drugs and cosmetic ingredients.

Animal testing of cosmetic ingredients and products has been banned in the European Union since 2013. However, in Japan, the application of new quasi-drugs requires the generation of data on acute oral toxicity through animal testing. A weight of evidence approach for assessing oral toxicity was challenged. This approach used a combination of safety data, including a neutral red uptake cytotoxicity assay using BALB/c3T3 cells (3T3-NRU cytotoxicity assay), which can assess the acute oral toxicity of quasi-drugs or cosmetic ingredients. We conclude that the step-by-step approach can be used to assess test substances that cause low acute oral toxicity, such as the median lethal dose (LD 50) > 2000 mg/kg, thereby avoiding animal testing.

Synthesis of trans-stilbenes via phosphine-catalyzed coupling reactions of benzylic halides.

An efficient and practical phosphine-catalyzed homo-coupling reaction of benzyl chlorides is described. The reactions proceed smoothly in the presence of CsF/B(OMe)3 and NaH as the base, respectively, to provide trans-stilbenes in good yields with a broad scope. Unsymmetrical stilbenes are also generated from the reactions of benzyl chlorides with phosphonium salts. Several P-based key intermediates have been detected by NMR and HRMS analyses, which shed light on the postulated catalytic cycle. In the presence of different bases, the transformations involve two different pathways, in which phenylcarbene and phosphonium alkoxide are considered as key intermediates, respectively. The two pathways are complementary in synthesis but different in mechanisms. The synthetic utility, including gram-scale reactions and straightforward access to π-conjugated molecules, has been demonstrated as well.

Palladium-Catalyzed Para-C-H Bond Amination of 2-Aryl Chloromethylbenzenes.

Palladium-catalyzed para-C-H bond amination of 2-aryl chloromethylbenzenes is described for the first time. The reactions of 2-aryl chloromethylbenzenes with cyclic amines proceeded smoothly in the presence of Pd(acac)2, tri(2-furyl)phosphine, and NaH in tetrahydrofuran at 40 °C to provide para-C-H bond aminated products in satisfactory to high yields with acceptable regioselectivity in most cases. The electronic property of the substituents linked to the benzene rings did not significantly influence the reactivity of the 2-aryl chloromethylbenzene substrates and the reaction regioselectivity.

Spirocarbocycle Synthesis from Chloromethylarenes via Transition-Metal-Catalyzed Allylative Dearomatization and Ring Closure Metathesis.

A strategy for the synthesis of spirocarbocycles by using chloromethyl arenes as starting materials is described in this paper. The palladium-catalyzed allylative dearomatization and the subsequent ruthenium-catalyzed ring closure metathesis proceeded smoothly under mild conditions to produce the corresponding spirocarbocycle products with moderate to high yields. Benzene-ring-, naphthalene-ring-, and anthracene-ring-containing substrates can be easily transformed into spirocarbocycles by using the proposed method.

Anterior Segmental Optical Coherence Tomography Analyses of Severe Corneal Irregular Astigmatism following Blepharoptosis Surgery.

We report a case of severe irregular corneal astigmatism resulting from delayed diagnosis of suture exposure following blepharoptosis surgery. An 81-year-old man who had bilateral blepharoptosis surgery and two revisions on his right eye before he complained foreign body sensation (FBS) and blurred vision of his right eye. The visual acuity was 0.4 and the MRD1 was 1 mm for his right eye. A very severe corneal astigmatism of 7.7D, eccentricity of 0.53, corneal thinning, and higher order aberration (HOA) of 3.346 µm was found. Scratch-like lesions on the upper cornea suggested the presence of suture exposure; however, no sutures were found by the previous physicians and at our fist ⇒ first examination. With greater effort, a large conjunctival fold on the back of upper tarsus was turned over to reveal 2 interrupted sutures protruding the palpebral conjunctiva. The sutures were removed, and the FBS quickly disappeared. However, the patient's blurred vision persisted. His right eye's visual acuity was 0.6, and the astigmatism (6.8D), eccentricity (0.72), and HOA (2.993 µm) were comparable to that before suture removal. Early diagnosis of suture exposure is critical to avoid severe complications and vision impairment. Attention should be paid to large conjunctival folds especially in re-operated cases.

Stable and Unstable Concentration Oscillations Induced by Temperature Oscillations on Reversible Nonequilibrium Chemical Reactions of Helicene Oligomers.

Temperature oscillations can affect behaviors of living things. In this article, we describe the effect of triangle temperature oscillations on reversible nonequilibrium chemical reactions detected as concentration oscillations. When amplification through self-catalytic reactions is involved in the chemical reactions, concentration oscillations exhibit diverse nonequilibrium phenomena, which include equilibrium intersecting, equilibrium noncontact, and equilibrium sliding. Both stable and unstable concentration oscillations occur, during which repeated cycles provide the same and different concentration oscillations, respectively. Concentration oscillations are classified according to their waveforms in concentration/time profiles, the shapes of hysteresis curves in concentration/temperature profiles, the nature of self-catalytic reactions, and their relationships with equilibrium. An unstable concentration oscillation may be transformed into a stable concentration oscillation, which is described on the basis of the classifications. Experimental examples are shown using reversible association and dissociation reactions of helicene oligomers.

The Effect of a Synthetic Estrogen, Ethinylestradiol, on the hERG Block by E-4031.

Inhibition of K+-conductance through the human ether-a-go-go related gene (hERG) channel leads to QT prolongation and is associated with cardiac arrhythmias. We previously reported that physiological concentrations of some estrogens partially suppress the hERG channel currents by interacting with the S6 residue F656 and increase the sensitivity of hERG blockade by E-4031. Although these studies suggested that clinically used synthetic estrogens with similar structures have the marked potential to alter hERG functions, the hERG interactions with synthetic estrogens have not been assessed. We therefore examined whether ethinylestradiol (EE2), a synthetic estrogen used in oral contraceptives, affects hERG function and blockade by drugs. Supratherapeutic concentrations of EE2 did not alter amplitudes or kinetics of the hERG currents elicited by train pulses at 20 mV (0.1 Hz). On the other hand, EE2 at therapeutic concentrations reduced the degree of hERG current suppression by E-4031. The administration of EE2 followed by E-4031 blockade reversed the current suppression, suggesting that the interaction of EE2 and E-4031 alters hERG at the drug-binding site. The effects of EE2 on hERG blockade raised the possibility that other estrogens, including synthetic estrogens, can alter hERG blockade by drugs that cause QT prolongation and ventricular arrhythmias.

[Analysis of contractile functions of human iPS-derived cardiomyocytes using motion field imaging].

Although the cardiotoxicity of anti-cancer drugs is an important issue, the underlying mechanisms remain unknown. To develop a sensitive assay system for cardiotoxicity, we examined effects of anticancer drugs on contractile functions of human iPS cell-derived cardiomyocytes by using non-invasive motion field imaging analysis with extended drug exposure time. We succeeded in continuously measuring stable contractile function. The continued exposure revealed that the difference in cardiotoxicity between cardiotoxic doxorubicin and less toxic erlotinib was more evident after 8 days of treatment than with 3 days of treatment, suggesting that continued exposure improved the predictive power for cardiotoxicity of anti-cancer drugs.

Thermal Hysteresis Involving Reversible Self-Catalytic Reactions.

Hysteresis is ubiquitous in nature and biology. It appears in ferromagnetism, ferroelectrism, traffic congestion, river sedimentation, electronics, thermoresponses, cell division, differentiation, and apoptosis. Hysteresis phenomena are beyond equilibrium and involve nonlinear, bistable, time delay, and memory events, which are described in input/output profiles by different outputs during continuous decreases and increases in input intensity. Although hysteresis profiles in these phenomena appear similar, the mechanisms underlying them are complex, and their basic understanding is desired. In this Account, I describe thermal hysteresis caused by molecules dispersed in dilute solutions containing optically active helicene oligomers, which form homo- and heterodouble helices, the cooling and heating processes of which cause different structural changes with regard to their relative concentrations. Reversible self-catalytic reactions are involved in the formation of a double helix, which catalyzes its own formation. The reactions accelerate as they progress, in contrast to ordinary reactions, which exhibit monotonic retardation as they progress. Thermal hysteresis involving reversible self-catalytic reactions exhibits notable phenomena, when various cooling/heating inputs are applied during the reaction; these phenomena are shown herein with profiles of experimental results of Δε outputs obtained by circular dichroism (CD) plotted against temperature inputs. Thermal hysteresis is discussed in terms of (1) two states of the homodouble helix and a random coil involving one reversible self-catalytic reaction and (2) three states of enantiomeric heterodouble helices and a random coil involving two reversible self-catalytic reactions. Repeated cooling and heating processes provide the same stable thermal hysteresis loops, when the initial and final high-temperature states are under equilibrium, and nonloop and unstable thermal hysteresis appears when whole the systems are beyond equilibrium. Diverse thermal hysteresis loops are obtained under different temperature change conditions for different oligomers. The mechanism of thermal hysteresis involves different macroscopic mechanisms at a fixed temperature, when the relative concentrations of substrates/products and the reaction direction differ. Microscopic mechanisms, which are shown by energy diagrams, are fixed at a temperature irrespective of cooling or heating. A comparison of thermal hysteresis loops and equilibrium curves provides distances to the metastable states on the loops from equilibrium, and reactions occur from the metastable states toward equilibrium. Notable phenomena described herein include bistability, high sensitivity to small concentration changes, equilibrium crossing, three-state one-directional structural change caused by a single heating procedure, reaction shortcuts, the memory effect on thermal history, figure-eight thermal hysteresis, chemical oscillation, stable and unstable thermal hysteresis, double-helix formation only under heating, and chiral symmetry breaking.

Corrigendum to "Retrospective Observational Study on Rebamipide Ophthalmic Suspension on Quality of Life of Dry Eye Disease Patients".

[This corrects the article DOI: 10.1155/2019/8145731.].

Synthetic Chemical Systems Involving Self-Catalytic Reactions of Helicene Oligomer Foldamers.

Self-catalysis is defined as catalysis by a product of a chemical reaction, that causes a significant increase in reaction rate in terms of the progress of the reaction. When a self-catalytic reaction is involved in a reversible nonequilibrium-to-equilibrium chemical reaction, notable kinetic phenomena appear including sigmoidal kinetics, the seeding effect, thermal hysteresis, and chiral symmetry breaking. The nature of self-catalytic reactions is characterized by microscopic mechanisms involving pathways of molecular structural changes and by macroscopic mechanisms involving molecular flux. Reversible self-catalytic reactions, which exhibit notably high sensitivity to environmental changes, are also observed. In this Review, reversible self-catalytic reactions of helicene oligomer foldamers during formation of homo- and hetero-double-helices are discussed, which exhibit the properties outlined above.

Rhodium-Catalyzed Synthesis of Organosulfur Compounds Involving S-S Bond Cleavage of Disulfides and Sulfur.

Organosulfur compounds are widely used for the manufacture of drugs and materials, and their synthesis in general conventionally employs nucleophilic substitution reactions of thiolate anions formed from thiols and bases. To synthesize advanced functional organosulfur compounds, development of novel synthetic methods is an important task. We have been studying the synthesis of organosulfur compounds by transition-metal catalysis using disulfides and sulfur, which are easier to handle and less odiferous than thiols. In this article, we describe our development that rhodium complexes efficiently catalyze the cleavage of S-S bonds and transfer organothio groups to organic compounds, which provide diverse organosulfur compounds. The synthesis does not require use of bases or organometallic reagents; furthermore, it is reversible, involving chemical equilibria and interconversion reactions.

Sequential self-catalytic reactions in the formation of hetero-double-helix and their self-assembled gels by pseudoenantiomer mixtures of ethynylhelicene oligomers.

A 1:1 mixture of pseudoenantiomer ethynylhelicene (P)-pentamer and (M)-tetramer in toluene formed hetero-double-helix and their self-assembled gels. Kinetic analysis under isothermal conditions showed a complex nonlinear nature with regard to temperature changes. At 60°C, sigmoidal kinetics were observed, which disappeared after seeding with the self-assembled gels. These findings indicate the involvement of self-catalytic reaction I, in which a hetero-double-helix catalyzes the reaction to form a hetero-double-helix from random-coils. At 20°C, stairwise biphasic kinetics were observed, which disappeared after seeding. This phenomenon was explained by the involvement of two reactions with sigmoidal kinetics, namely, the formation of self-assembled gel I from hetero-double-helix by self-catalytic reaction II and the formation of self-assembled gel II by self-catalytic reaction III. Constant-rate temperature change experiments between 90 and 5°C showed nonsigmoidal thermal hysteresis in accordance with the involvement of sequential self-catalytic reactions with different reaction rates.

Rhodium-catalyzed phosphorylation reaction of water-soluble disulfides using hypodiphosphoric acid tetraalkyl esters in water.

RhCl3 catalyzed the exchange reaction of disulfides and hypodiphosphoric acid tetraalkyl esters in water under homogeneous conditions, which indicated the hypodiphosphoric acid tetraalkyl esters to be novel and efficient phosphorylation reagents in water. The reaction was used in the phosphorylation of unprotected glutathione disulfide.

Figure-eight thermal hysteresis of aminomethylenehelicene oligomers with terminal C16 alkyl groups during hetero-double-helix formation.

1 : 1 mixtures of aminomethylenehelicene (P)-tetramer and (M)-pentamer with terminal C16 alkyl groups in fluorobenzene showed structural changes between hetero-double-helices B and C and random-coils 2A. Figure-eight thermal hysteresis appeared when the solution was cooled and heated at a constant rate and involved the crossing of cooling and heating curves in Δε/temperature profiles. This unusual thermal hysteresis emerged in the intermediate state between counterclockwise and clockwise thermal hystereses. This phenomenon arose from the competition between self-catalytic reactions to form B and C from 2A. Significant effects of terminal C16 alkyl groups on the thermodynamic and kinetic phenomena are also described.

Acid-catalyzed synthesis of condensed polycyclic diaryl ethers from arenols.

Diaryl ethers containing condensed polycyclic aryl groups were synthesized from arenols in the presence of a catalytic amount of p-chlorobenzenesulfonic acid. Symmetrical binaphthyl, biphenanthryl, and bipyrenyl ethers were obtained in high yields. Unsymmetrical derivatives were also synthesized from 9-phenanthrol and arenols, using combinations of reactive and unreactive substrates.

Proximate stochastic chiral symmetry breaking is mechanically tunable: formation of enantiomeric hetero-double-helices and aggregates from racemic oxymethylenehelicene oligomers.

A mixture of oxymethylenehelicene (P)-hexamer and (M)-hexamer in solution exhibited chiral symmetry breaking, which was induced by mechanical stirring, during the formation of enantiomeric hetero-double-helices and their aggregates. A racemic 50 : 50 mixture was heated to 90 °C to form a dissociated state, and then cooled to 25 °C. Mechanical stirring with a magnetic stirrer at 2000 rpm for 100 h resulted in the exhibition of a strong negative Cotton effect at 322 nm. Repeated experiments provided negative Cotton effects, which is due to the deterministic chiral symmetry breaking. No change in the Cotton effect occurred in the absence of stirring. The (P)-hexamer to (M)-hexamer mixing molar fraction was varied, and a positive Cotton effect appeared at molar fractions between 40 : 60 and 46 : 54 and a negative Cotton effect at molar fractions between 48 : 52 and 60 : 40, which was reversed at 47 : 53. The slight deviation of symmetry from that at 50 : 50 was termed proximate stochastic chiral symmetry breaking. The process of chiral symmetry breaking could be tuned by varying the procedures of mechanical stirring and mixing procedures for solutions of (P)-hexamer and/or (M)-hexamer.

Continued exposure of anti-cancer drugs to human iPS cell-derived cardiomyocytes can unmask their cardiotoxic effects.

Although the cardiotoxicity of anti-cancer drugs is an important issue, the underlying mechanisms remain unknown. To develop a sensitive assay system for cardiotoxicity, we examined effects of anti-cancer drugs on contractile functions of human iPS cell-derived cardiomyocytes by using non-invasive motion field imaging analysis with extended drug exposure time. We succeeded in continuously measuring stable contractile function. The continued exposure revealed that the difference in cardiotoxicity between cardiotoxic doxorubicin and less toxic erlotinib was more evident after 8 days of treatment than with 3 days of treatment, suggesting that continued exposure improved the predictive power for cardiotoxicity of anti-cancer drugs.