Recent advancement in the synthesis of isothiocyanates.

Isothiocyanates exhibit various biological characteristics, including antimicrobial, anti-inflammatory, and anticancer properties. Their significance extends to synthetic chemistry, where they serve as valuable platforms for versatile transformations. Consequently, they have attracted the attention of biologists and chemists. This review summarizes recent advancements in the synthesis of isothiocyanates. Access to a variety of starting materials is important to prepare isothiocyanates with diverse structures. This review categorizes synthetic methods into three types based on the starting materials and functional groups: (i) type A, derived from primary amines; (ii) type B, derived from other nitrogen functional groups; and (iii) type C, derived from non-nitrogen groups. Recent trends in synthetic methods have revealed the prevalence of type-A reactions derived from primary amines. However, type B reactions have rarely been reported. Notably, over the past four years, there has been a notable increase in type C reactions, indicating a growing interest in non-nitrogen-derived isothiocyanates. Overall, this review not only outlines the advancements in the synthesis of isothiocyanates but also highlights trends in the methodology.

Functionalized Polyamine Synthesis with Photoredox Catalysis.

Polyamines, such as putrescine and spermidine, are pivotal in various biological processes across living organisms. Despite their significance, structurally modified polyamines offer a less-explored avenue for discovering bioactive compounds. The limitation is attributed to the synthetic difficulty of accessing functionalized polyamines. In this study, we accomplished photoredox-catalyzed functionalization of polyamines to diversify their structure. The rapid functionalization allows attaching fluorophores to the target polyamine, facilitating the development of molecular probes for advancing chemical biology studies.

Switchable Decarboxylation by Energy- or Electron-Transfer Photocatalysis.

Kolbe dimerization and Hofer-Moest reactions are well-investigated carboxylic acid transformations, wherein new carbon-carbon and carbon-heteroatom bonds are constructed via electrochemical decarboxylation. These transformations can be switched by choosing an electrode that allows control of the reactive intermediate, such as carbon radical or carbocation. However, the requirement of a high current density diminishes the functional group compatibility with these electrochemical reactions. Here, we demonstrate the photocatalytic decarboxylative transformation of activated carboxylic acids in a switchable and functional group-compatible manner. We discovered that switching between Kolbe-type or Hofer-Moest-type reactions can be accomplished with suitable photocatalysts by controlling the reaction pathways: energy transfer (EnT) and single-electron transfer (SET). The EnT pathway promoted by an organo-photocatalyst yielded 1,2-diarylethane from arylacetic acids, whereas the ruthenium photoredox catalyst allows the construction of an ester scaffold with two arylmethyl moieties via the SET pathway. The resulting radical intermediates were coupled to olefins to realize multicomponent reactions. Consequently, four different products were selectively obtained from a simple carboxylic acid. This discovery offers new opportunities for selectively synthesizing multiple products via switchable reactions using identical substrates with minimal cost and effort.

Copper-catalyzed reaction of aziridine for the synthesis of substituted imidazolidine and imidazolidinone.

Herein we report a copper-catalyzed synthesis of imidazolidine by employing the reaction of aziridine with imine. The reaction smoothly provided a diverse range of 2-substituted imidazolidines with high compatibility with various functional groups. Moreover, during our investigation, we discovered that isocyanate also reacted with aziridine to yield substituted imidazolidinones efficiently. The versatility of these reactions was further demonstrated by their application in the synthesis of hybrid molecules derived from two pharmaceutical compounds. This approach opens new possibilities for the discovery of novel classes of bioactive molecules.

Divergent Synthesis of Stachyurin and Casuarinin Focusing on C-Glycosidic Bond Reactivity.

Stachyurin and casuarinin are ellagitannins, a class of polyphenols that exhibit various biological activities that have an impact on human health. Casuarinin is a stachyurin stereoisomer. These compounds contain the characteristic C-glycosidic bond between the open-chain d-glucose and the phenol aromatic ring. Therefore, chemical elucidation of the C-glycosidic bond reactivity is required to exploit their multiple bioactivities. This study developed a method for the divergent synthesis of stachyurin and casuarinin via the α-selective C-glycosylation as well as the ß-selective introduction of the oxygen functional group, focusing on structural specificity. The proposed method applies to the syntheses of stachyurin and casuarinin analogues, thereby facilitating the utilisation of their beneficial bioactivities.

Copper-Catalyzed Heterocyclic Recombination of Aziridine and Diazetidine for the Synthesis of Imidazolidine.

The discovery of new catalytic applications for metals remains an important goal in organic synthesis. If a catalyst has multiple functions, such as inducing bond cleavage and formation, it can streamline multi-step transformations. Herein, the Cu-catalyzed synthesis of imidazolidine through heterocyclic recombination between aziridine and diazetidine is reported. Mechanistically, Cu catalyzes the conversion of diazetidine into the corresponding imine, which then reacts with aziridine to form imidazolidine. The scope is sufficiently wide to form various imidazolidines, as many functional groups are compatible with the reaction conditions.

Identification and improvement of isothiocyanate-based inhibitors on stomatal opening to act as drought tolerance-conferring agrochemicals.

Stomatal pores in the plant epidermis open and close to regulate gas exchange between leaves and the atmosphere. Upon light stimulation, the plasma membrane (PM) H+-ATPase is phosphorylated and activated via an intracellular signal transduction pathway in stomatal guard cells, providing a primary driving force for the opening movement. To uncover and manipulate this stomatal opening pathway, we screened a chemical library and identified benzyl isothiocyanate (BITC), a Brassicales-specific metabolite, as a potent stomatal-opening inhibitor that suppresses PM H+-ATPase phosphorylation. We further developed BITC derivatives with multiple isothiocyanate groups (multi-ITCs), which demonstrate inhibitory activity on stomatal opening up to 66 times stronger, as well as a longer duration of the effect and negligible toxicity. The multi-ITC treatment inhibits plant leaf wilting in both short (1.5 h) and long-term (24 h) periods. Our research elucidates the biological function of BITC and its use as an agrochemical that confers drought tolerance on plants by suppressing stomatal opening.

Incidence of Mid-Term Prognostic Events in Patients With Acute Coronary Syndrome During the Late 2010s in 2 Tertiary Hospitals in a Rural Area of Japan　- A Temporal Comparison.

Background: Data on the incidence of mid-term prognostic events in patients who developed acute coronary syndrome (ACS) in the late 2010s are scarce. Methods and Results: We retrospectively included and collected data for 889 patients with ACS (ST-elevation myocardial infarction [STEMI]/non-ST-elevation ACS [NSTE-ACS]) discharged alive from 2 tertiary hospitals in Izumo City, in rural Japan, between August 2009 and July 2018. Patients were divided into 3 time groups (T1: August 2009-July 2012; T2: August 2012-July 2015; T3: August 2015-July 2018). The cumulative incidence of major adverse cardiovascular events (MACE; comprising all-cause death, recurrent ACS, and stroke), major bleeding, and heart failure hospitalization within 2 years of discharge was compared among the 3 groups. The incidence of freedom from MACE was significantly higher in the T3 group than in the T1 and T2 groups (93 [95% confidence interval {CI} 90-96%] vs. 86% [95% CI 83-90] and 89% [95% CI 90-96], respectively; P=0.03). There was a tendency for a higher incidence of STEMI among patients in T3 (P=0.057). The incidence of NSTE-ACS was comparable among the 3 groups (P=0.31), as was the incidence of major bleeding and hospitalization for heart failure. Conclusions: The incidence of mid-term MACE in patients who developed ACS during the late 2010 s (2015-2018) was lower than that in prior periods (2009-2015).

Verification of Biaryl-Structure Axial Chirality Produced in Ellagitannins by Chemical Oxidation.

The axial chirality of hexahydroxydiphenoyl (HHDP) groups contained in ellagitannins depends on the bridging position of d-glucose. The 4,6-O-HHDP group predominantly exhibits S-type chirality. This study elucidated the formation of the 4,6-O-(R)-HHDP group and subsequent axial isomerization by means of oxidative coupling of galloyl groups, which resulted in S chirality.

Photoinduced Synthesis of Thiocyanates through Hydrogen Atom Transfer and One-Pot Derivatization to Isothiocyanates.

Photoinduced benzylic C-H thiocyanation is described. A series of alkyl thiocyanates were efficiently obtained by using Selectfluor as the oxidant. Moreover, we accomplished the one-pot isothiocyanation following the C-H thiocyanation. The thiocyanates and isothiocyanates were applied to the divergent transformation of pharmaceuticals.

Ultrasonic cleaning is effective in removing carbonized clots and tissue from the insulation-tipped diathermic knife-2.

Objectives: Since carbonized clots and tissue (debris) tend to adhere firmly to the tip of the endoscopic submucosal dissection (ESD) knife as the procedure proceeds, manual removing the firm debris is often challenging and time-consuming. Recently, effective ultrasonic cleaning for other medical devices has been reported. The aim of the present study was to clarify whether ultrasonic cleaning is effective in removing the debris on the insulation-tipped diathermic (IT) knife-2. Methods: This study was an ex-vivo experimental randomized study. A total of 40 IT knife-2 knives with debris on their tip surfaces were prepared and randomly assigned to two groups (Group A and Group B). The knives in Group A were cleaned using the conventional scrubbing method for 30 s (conventional cleaning method), while those in Group B were cleaned using a combined method of scrubbing for 20 s and ultrasonic cleaning for 10 s (combined ultrasonic cleaning method). The tip electrode of the knife after cleaning was photographed under a microscope (40x). The 40 images of the knives were evaluated by independent three endoscopists and two clinical engineers using the five-step evaluation criteria ranging from cleaning score 1 (dirty) to 5 (clean). Results: The mean cleaning score of 3.78 (range: 2.33-4.67) in Group B was significantly higher than that of 1.68 (range: 1.00-2.83) in Group A. Conclusions: The combined ultrasonic cleaning method could remove debris adhering to the IT knife-2 more effectively than the conventional cleaning method. Ultrasonic cleaning may be applied for real-world ESD.

Central nervous system stimulants promote nerve cell death under continuous hypoxia.

Intake of central nervous system (CNS) stimulants causes hypoxia and brain edema, which results in nerve cell death. However, no study has yet investigated the direct and continuous effects on nerve cells of CNS stimulants under hypoxia. Thus, based on autopsy cases, the effects of CNS stimulant drugs on the CNS were examined. The pathological changes in cultured nerve cells when various CNS stimulants were added under a hypoxic condition were also investigated. Five groups (Group A, stimulants; Group B, stimulants with psychiatric drugs; Group C, caffeine; Group D, psychiatric drugs; and Group E, no drugs) according to the detected drugs in autopsy cases were compared, and brain edema was evaluated using morphological findings. Furthermore, the number of dead cultured nerve cells was counted after the addition of drugs (4-aminopyridine (4-AP), caffeine, and ephedrine) under hypoxia (3% O2). Staining with anti-receptor-interacting protein 3 (RIP3) and other associated stains was also performed to investigate the neuronal changes in the brain. Group A showed significantly more brain edema than the other groups. In the culture experiments, the ratio of nerve cell death after the addition of 4-AP was the highest in the hypoxic condition. Groups with stimulants detected were stained more strongly by RIP3 immunostaining than by other staining. Addition of stimulants to cultured nerve cells in a persistent hypoxic condition led to severe cytotoxicity and nerve cell death. These findings suggest that necroptosis is involved in nerve cell death due to the addition of CNS stimulants in the hypoxic condition.

Synthesis of octagon-containing molecular nanocarbons.

Nanocarbons, such as fullerenes, carbon nanotubes, and graphenes, have long inspired the scientific community. In order to synthesize nanocarbon molecules in an atomically precise fashion, many synthetic reactions have been developed. The ultimate challenge for synthetic chemists in nanocarbon science is the creation of periodic three-dimensional (3D) carbon crystals. In 1991, Mackay and Terrones proposed periodic 3D carbon crystals with negative Gaussian curvatures that consist of six- and eight-membered rings (the so-called Mackay-Terrones crystals). The existence of the eight-membered rings causes a warped nanocarbon structure. The Mackay-Terrones crystals are considered a "dream material", and have been predicted to exhibit extraordinary mechanical, magnetic, and optoelectronic properties (harder than diamond, for example). To turn the dream of having this wonder material into reality, the development of methods enabling the creation of octagon-embedding polycyclic structures (or nanographenes) is of fundamental and practical importance. This review describes the most vibrant synthetic achievements that the scientific community has performed to obtain curved polycyclic nanocarbons with eight-membered rings, building blocks that could potentially give access as templates to larger nanographenes, and eventually to Mackay-Terrones crystals, by structural expansion strategies.

Central Nervous System Stimulants Limit Caffeine Transport at the Blood-Cerebrospinal Fluid Barrier.

Caffeine, a common ingredient in energy drinks, crosses the blood-brain barrier easily, but the kinetics of caffeine across the blood-cerebrospinal fluid barrier (BCSFB) has not been investigated. Therefore, 127 autopsy cases (Group A, 30 patients, stimulant-detected group; and Group B, 97 patients, no stimulant detected group) were examined. In addition, a BCSFB model was constructed using human vascular endothelial cells and human choroid plexus epithelial cells separated by a filter, and the kinetics of caffeine in the BCSFB and the effects of 4-aminopyridine (4-AP), a neuroexcitatory agent, were studied. Caffeine concentrations in right heart blood (Rs) and cerebrospinal fluid (CSF) were compared in the autopsy cases: caffeine concentrations were higher in Rs than CSF in Group A compared to Group B. In the BCSFB model, caffeine and 4-AP were added to the upper layer, and the concentration in the lower layer of choroid plexus epithelial cells was measured. The CSF caffeine concentration was suppressed, depending on the 4-AP concentration. Histomorphological examination suggested that choroid plexus epithelial cells were involved in inhibiting the efflux of caffeine to the CSF. Thus, the simultaneous presence of stimulants and caffeine inhibits caffeine transfer across the BCSFB.

C-H Acyloxylation of Polycyclic Aromatic Hydrocarbons.

The C-H acyloxylation of polycyclic aromatic hydrocarbons (PAHs) is described. This reaction constructs aryl acyloxylate scaffolds from PAHs with equimolar hypervalent iodine compounds under mild reaction conditions. Interestingly, the blue light irradiation accelerated this transformation. Additionally, the synthesis of structurally new symmetric and unsymmetric diaroyloxylated fluoranthenes was accomplished with a ruthenium photoredox catalyst.

Identification of stomatal-regulating molecules from de novo arylamine collection through aromatic C-H amination.

Stomata-small pores generally found on the leaves of plants-control gas exchange between plant and the atmosphere. Elucidating the mechanism that underlies such control through the regulation of stomatal opening/closing is important to understand how plants regulate photosynthesis and tolerate against drought. However, up-to-date, molecular components and their function involved in stomatal regulation are not fully understood. We challenged such problem through a chemical genetic approach by isolating and characterizing synthetic molecules that influence stomatal movement. Here, we describe that a small chemical collection, prepared during the development of C-H amination reactions, lead to the discovery of a Stomata Influencing Molecule (SIM); namely, a sulfonimidated oxazole that inhibits stomatal opening. The starting molecule SIM1 was initially isolated from screening of compounds that inhibit light induced opening of dayflower stomata. A range of SIM molecules were rapidly accessed using our state-of-the-art C-H amination technologies. This enabled an efficient structure-activity relationship (SAR) study, culminating in the discovery of a sulfonamidated oxazole derivative (SIM*) having higher activity and enhanced specificity against stomatal regulation. Biological assay results have shed some light on the mode of action of SIM molecules within the cell, which may ultimately lead to drought tolerance-conferring agrochemicals through the control of stomatal movement.

Clinical effectiveness of implant support for distal extension removable partial dentures: functional evaluation using occlusal force measurement and masticatory efficiency.

BACKGROUND: Implant-supported removable partial dentures (ISRPD) are supported at the free-end region with implant retainers. As implant retainers prevent denture settlement and facilitate denture retention, this is intended to improve masticatory performance in comparison with that of conventional removable dentures. In the present study, we evaluated the effect of implant retainers at the free-end region of removable dentures on occlusal force and masticatory efficiency using a pressure-sensitive sheet, and measured glucose concentration in saliva after mastication with gummy candy. METHODS: In the present study, the occlusal force and masticatory efficiency of 13 subjects were measured in the following three conditions: without dentures (Condition 1), wearing dentures but not supported by implants (Condition 2), and wearing dentures supported by implants (ISRPD) (Condition 3). All data were statistically compared. RESULTS: Regarding the occlusal force, Condition 3 showed significantly higher scores than the other conditions; however, there were no significant differences between Conditions 1 and 2. Regarding the masticatory efficiency, Condition 3 showed significantly higher scores than Condition 2. CONCLUSIONS: With ISRPD, the occlusal force and masticatory efficiency were increased in comparison with those with conventional removable dentures.

Discovery of bactericides as an acute mitochondrial membrane damage inducer.

Mitochondria evolved from endosymbiotic bacteria to become essential organelles of eukaryotic cells. The unique lipid composition and structure of mitochondrial membranes are critical for the proper functioning of mitochondria. However, stress responses that help maintain the mitochondrial membrane integrity are not well understood. One reason for this lack of insight is the absence of efficient tools to specifically damage mitochondrial membranes. Here, through a compound screen, we found that two bis-biguanide compounds, chlorhexidine and alexidine, modified the activity of the inner mitochondrial membrane (IMM)-resident protease OMA1 by altering the integrity of the IMM. These compounds are well-known bactericides whose mechanism of action has centered on their damage-inducing activity on bacterial membranes. We found alexidine binds to the IMM likely through the electrostatic interaction driven by the membrane potential as well as an affinity for anionic phospholipids. Electron microscopic analysis revealed that alexidine severely perturbated the cristae structure. Notably, alexidine evoked a specific transcriptional/proteostasis signature that was not induced by other typical mitochondrial stressors, highlighting the unique property of alexidine as a novel mitochondrial membrane stressor. Our findings provide a chemical-biological tool that should enable the delineation of mitochondrial stress-signaling pathways required to maintain the mitochondrial membrane homeostasis.

Photoredox-Catalyzed Benzylic Esterification via Radical-Polar Crossover.

Photoredox-catalyzed C-O bond formation reactions are reported. The decarboxylative esterification reaction allows the conversion of a variety of arylacetic acids into the corresponding benzyl carboxylates. Furthermore, the use of (diacetoxyiodo)benzene allows the conversion of the benzylic C-H bond through hydrogen atom transfer. The reactions were applied to the divergent transformation of pharmaceuticals via decarboxylative or C-H esterification reactions.