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[Display omitted] • 6-shogaol improved motor and memory deficits in the aged mice. • 6-shogaol attenuated neurodegeneration and neuroinflammation in the aged mice. • 6-shogaol inhibited p75 neurotrophin receptor expression in the brain of aged mice. The present study aimed to investigate the effect of 6-shogaol (6S) treatment on brain senescence. Mice were naturally aged until 25-month-old and treated with 10 mg/kg of 6S for a month. Behavioral tests were performed to measure locomotion and cognitive function. Neuronal damage, synaptic plasticity, neuroinflammation, neurogenesis and p75 neurotrophin receptor (p75NTR) expression were examined by immunohistochemistry or immunofluorescence. 6S treatment improved locomotion during open field test in the aged mice and spontaneous alternation in Y-maze. These data are in line with that 6S administration improved dopaminergic neuronal loss and dopamine signaling and attenuated hippocampal synaptic plasticity in the aged brain. Additionally, 6S treatment reduced striatal and hippocampal microgliosis and astrocytosis but promoted neurogenesis in subventricular zone. Furthermore, 6S treatment reversed the p75NTR expression in the senescent brain. The current findings suggest that 6S can be a functional food for successful aging through brain rejuvenation at the molecular level. [ABSTRACT FROM AUTHOR]

Photodynamic therapy is a clinically approved treatment approach for cancer. However, it has limited applications owing to poor water solubility and the short wavelength absorption of the photosensitizer (PS). We selected a near-infrared photosensitizer, SiNC, and encapsulated into a gold nanocage (AuNC) in the presence of phase-changing material. Then, the PS-encapsulated nanocage was coated with glycol chitosan (GC) with a cleavable peptide linkage or stable cysteine linkage to protect the PS from premature release and to improve the biocompatibility of the nanocage. We obtained particles of GC-coated SiNC-encapsulated AuNC with a neutral surface charge and approximately 160 nm in size. The enzyme-cleavable peptide-linked GC formulation (GC-pep@SiNC-AuNC) showed stronger phototoxicity and tumor suppression efficacy in a glioblastoma model compared with free NIR-PS and stable cysteine-linked GC-AuNC (GC-cys@SiNC-AuNC). This polymer-coated SiNC-AuNC may be a promising agent for brain cancer phototherapy. Near infrared photosensitizer-encapsulated gold nanocage was prepared and coated with glycol chitosan with stimuli-responsive or stable peptide linkage. The nanoformulation was found to have around 120-160 nm in size and neutral surface charge. In vitro and in vivo study in brain tumor showed that this formulation has a great combined phototherapy activity. Unlabelled Image [ABSTRACT FROM AUTHOR]

The present study reports the cancer chemopreventive activities of phenyl polyyne diols derived from polyacetylene triol. Thirty-seven analogues based on a 1-phenylhexa-2,4-diyne-1,6-diol scaffold were prepared and their effects on QR activity were elucidated, as well as their cytotoxicities. We found that most of the derivatives based on phenylhexa-2,4-diyne-1,6-diol exhibited good QR induction activity and relatively low cytotoxicity and systemic structure–activity relationship was revealed. In particular, 4-fluorophenyl, 3-chlorophenyl, and 3,4-dioxolophenyl derivatives showed the best profiles in terms of QR induction, cytotoxicity, and CI. [ABSTRACT FROM AUTHOR]

Abstract: We synthesized diyne triols based on gymnasterkoreayne and evaluated their cancer chemopreventive activities in terms of the chemopreventive index (CI) to reveal the structure–activity relationship, and discovered more active compounds than natural diynes. [ABSTRACT FROM AUTHOR]

Abstract: 2-Iminothiazole, an isoform of 2-aminothiazole, is a scaffold of synthetic and medicinal significance. We have reported an efficient method by which alkyl group of 2-alkyliminothiazoles is changed into other alkyl groups by isothiocyanates. In this article, a detailed mechanistic aspect, and the scopes and limitations were disclosed. All the reactions were carried out in toluene at 105°C without any additive. The reaction is a reversible process and the equilibrium is determined by the reactivity of both reactants, in which the more electron-withdrawing alkyl or aryl groups at the 2-imino group or isothiocyanate showed higher reactivities. With this simple method, we effectively altered the alkyl group attached on the imine nitrogen. A synthetic problem in 2-iminothiazole chemistry, synthesis of amino acid-derived 2-iminothiazole was solved in a very simple manner. Using suitably designed 2-iminothiazole substrate, the electrophilic reactivity of various isothiocyanates could be empirically compared by this exchange reaction. Moreover, successful exchange reaction using isocyanates instead of isothiocyanates broadened the utility of this reaction. [ABSTRACT FROM AUTHOR]

Abstract: The magnetization switching phenomena of GaMnAs Hall devices have been investigated by using the planar Hall effect (PHE) measurement. Though two different sizes of Hall bar devices, width of 300 and of 10μm, show very similar Curie temperature, their magnetization switching fields behave significantly different. While the angle dependence of magnetization switching field of the 300μm device showed typical rectangular shape behavior with an applied magnetic field angle in the polar plot, that of the 10μm device exhibited large step at 〈110〉 crystallographic directions, breaking the continuity of the switching field in angle dependence. Such unusual phenomenon observed in the 10μm device was discussed in terms of the change in magnetic anisotropy by the fabrication of micro-device. [Copyright &y& Elsevier]

• The effect of ambient pressure on the spray generated by a hybrid pressure-swirl airblast atomizer was investigated using standard and alternative aviation fuels. • Liquid/vapor phase discrimination was performed using fuel-Planar Laser Induced Fluorescence (PLIF) and Mie scattering images. • The feasibility of the laser sheet drop-sizing (LSD) technique using LIF/Mie signal ratio was examined for the spray at high ambient pressure application. • A semi-empirical model was developed to provide insights into the effect of ambient pressure on the drop formation. The spray characteristics of standard and alternative aviation fuels generated by a hybrid pressure-swirl airblast (HPSA) atomizer were investigated at high ambient pressure conditions. The measurements were performed in an optically accessible pressure vessel at pressures of 1, 2, 3, 4, 5, and 9.5 bar with heated gas and fuel temperatures of 394 K and 332 K, respectively. The drop size and drop velocity of sprays from a standard (Jet-A) and an alternative (C-5) aviation fuels were measured using phase Doppler anemometry (PDA), and 2-D visualization of spray was imaged using simultaneous fuel-Planar Laser Induced Fluorescence (PLIF) and Mie scattering. The spatially resolved PDA drop size measurements were obtained at 25.4 mm downstream of the swirler exit plane and up to 30 mm in the radial direction from the spray centerline. The Sauter Mean Diameter (D 32) was observed to decrease significantly with increasing ambient pressure, up to 5 bar. However, the change in D 32 was observed to be limited with a further increase in the ambient pressure. A higher swirler pressure drop resulted in a significant reduction in the D 32 at an ambient pressure of 5 bar. Using simultaneous fuel-PLIF and Mie scattering imaging, the feasibility of the laser sheet drop-sizing (LSD) technique was examined for the spray at high ambient pressure application. In addition, the effect of ambient pressure on the spray cone angle was investigated using both instantaneous and averaged Mie images. The distribution of fuel vapor and droplets in the spray was also imaged and identified by comparing instantaneous fuel-PLIF and Mie images. A phenomenological three-step atomization model was used to predict the drop size and demonstrate the drop size trend with increasing ambient pressure. [ABSTRACT FROM AUTHOR]

Abstract: Novel alkyl/aryl transposition in the reaction of 2-iminothiazoles with alkyl/aryl isothiocyanates was found out, and the reaction was very easy to handle and gave good to excellent chemical yields. Moreover, transposition reaction provided a simple but excellent solution for regiochemical problems in 2-iminothiazole synthesis. [Copyright &y& Elsevier]

Abstract Hydantoin, imidazolidine-2,4-dione, is a non-aromatic five-membered heterocycle, which is considered a valuable, privileged scaffold in medicinal chemistry. The importance of the hydantoin scaffold in drug discovery has been reinforced by several medicines in clinical use, such as phenytoin, nitrofurantoin, and enzalutamide. Hydantoin has five potential substituent sites, including two hydrogen bond acceptors and two hydrogen bond donors. Two additional attractive features of hydantoin scaffolds are their synthetic feasibility for core scaffolds via established cyclization reactions and their ease of accepting various substituents. Because of these characteristics, many hydantoin derivatives with different substituents have been designed and synthesized and exhibit a broad spectrum of biological and pharmacological activities against, for example, cancers, microbial infections, metabolic diseases, and epilepsy. In this review, recent contributions of hydantoin, thiohydantoin, and selenohydantoin scaffolds to medicinal chemistry are described; some major compounds are presented to emphasize their importance, and their structure-activity relationships (SARs) are briefly addressed. Major discussions are devoted to the structural features or novelty of each scaffold and its SAR. The publications in this review encompass those from 2012 to 2018. Graphical abstract Image 1 Highlights • Recent applications of (thio)hydantoin scaffold in medicinal chemistry and drug discovery. • (Thio)hydantoins as useful scaffold in medicinal chemistry due to their synthetic feasibility and versatility of substituents. • Brief structure-activity relationship for each biological activity. [ABSTRACT FROM AUTHOR]

A large number of protozoans infect humans but Entamoeba histolytica is the only organism responsible for causing amoebiasis, a deadly disease after malaria. Numerous heterocycle-based antiamoebic agents have been previously synthesized as E. histolytica inhibitors and while some of these agents have shown moderate activity, the search for a novel and ideal antiamoebic compound is still ongoing. In this digest Letter, we present the latest data on antiamoebic agents from 2011 to 2016 based on the different classes of heterocyclic agents. [ABSTRACT FROM AUTHOR]

Macrocycles are defined as cyclic compounds with 12 or more members. In medicinal chemistry, they are categorized based on their core chemistry into cyclic peptides and macrocycles. Macrocycles are advantageous because of their structural diversity and ability to achieve high affinity and selectivity towards challenging targets that are often not addressable by conventional small molecules. The potential of macrocyclization to optimize drug-like properties while maintaining adequate bioavailability and permeability has been emphasized as a key innovation in medicinal chemistry. This review provides a detailed case study of the application of macrocyclization over the past 5 years, starting from the initial analysis of acyclic active compounds to optimization of the resulting macrocycles for improved efficacy and drug-like properties. Additionally, it illustrates the strategic value of macrocyclization in contemporary drug discovery efforts. [Display omitted] • We summarized macrocyclization strategy from acyclic precursors aimed at improving candidate profile from 2019 to 2023. • We specifically emphasized rationale behind the design strategy of macrocyclization based on X-ray crystallography or molecular modelling. • Improvements or changes of activities or DMPK-Tox profiles of resulting macrocycles were compared with acyclic precursors. [ABSTRACT FROM AUTHOR]

Abstract: The human ether-à-go-go related gene potassium channel is a key player in cardiac rhythm regulation, thus being an important subject for a cardiac toxicity test. Ever since human ether-à-go-go related gene channel inhibition-related cardiac arrest was proven to be fatal, numerous numbers of data on human ether-à-go-go related gene channel inhibition have been piled up. However, there has been no quantitative study on human ether-à-go-go related gene channel inhibition by quaternary ammonium derivatives, well-known potassium channel blockers. Here, we present human ether-à-go-go related gene channel blockade by externally applied quaternary ammonium derivatives using automated whole-cell patch-clamp recordings as well as ab initio quantum calculations. The inhibitory constants and the relative binding energies for human ether-à-go-go related gene channel inhibition were obtained from quaternary ammoniums with systematically varied head and tail groups, indicating that more hydrophobic quaternary ammoniums have higher affinity blockade while cation-π interactions or size effects are not a deterministic factor for human ether-à-go-go related gene channel inhibition by quaternary ammoniums. Further studies on the effect of quaternary ammoniums on human ether-à-go-go related gene channel inactivation implied that hydrophobic quaternary ammoniums either with a longer tail group or with a bigger head group than tetraethylammonium permeate the cell membrane to easily access the high-affinity internal binding site in human ether-à-go-go related gene channel and exert stronger blockade. These results may be informative for the rational drug design to avoid cardiac toxicity. [Copyright &y& Elsevier]

Graphical abstract Highlights • Design and synthesis of novel GCGR antagonists as pyrimidine derivatives. • The compound of (R) -7a decreased the glucagon-induced cAMP production. • The compound of (R) -7a decreased the glucagon-induced glucose production. • The compound of (R) -7a decreased the glucagon-induced glucose excursion in vivo. • The compound of (R) -7a lowering fasting blood glucose levels in db / db mice. Abstract The hormone glucagon increases blood glucose levels through increasing hepatic glucose output. In diabetic patients, dysregulation of glucagon secretion contributes to hyperglycemia. Thus, the inhibition of glucagon receptor is one target for the treatment of hyperglycemia in type 2 diabetes. Here we designed and synthesized a series of small molecules based on phenylpyrimidine. Of these, the compound (R) -7a most significantly decreased the glucagon-induced cAMP production and glucagon-induced glucose production during in vitro and in vivo assays. In addition, (R) -7a showed good efficacy in glucagon challenge tests and lowered blood glucose levels in diabetic db/db mice. Our results suggest that the compound (R) -7a could be a potential glucose-lowering agent for treating type 2 diabetes. [ABSTRACT FROM AUTHOR]

In an endeavor to develop efficacious antiprotozoal agents 4-(7-chloroquinolin-4-yl) piperazin-1-yl)pyrrolidin-2-yl)methanone derivatives ( 5 – 14 ) were synthesized, characterized and biologically evaluated for antiprotozoal activity. The compounds were screened in vitro against the HM1: IMSS strain of Entamoeba histolytica and NF54 chloroquine-sensitive strain of Plasmodium falciparum. Among the synthesized compounds six exhibited promising antiamoebic activity with IC 50 values (0.14–1.26 μM) lower than the standard drug metronidazole (IC 50 1.80 μM). All nine compounds exhibited antimalarial activity (IC 50 range: 1.42–19.62 μM), while maintaining a favorable safety profile to host red blood cells. All the compounds were less effective as an antimalarial and more toxic (IC 50 range: 14.67–81.24 μM) than quinine (IC 50 : 275.6 ± 16.46 μM) against the human kidney epithelial cells. None of the compounds exhibited any inhibitory effect on the viability of Anopheles arabiensis mosquito larvae. [ABSTRACT FROM AUTHOR]

Aim of the study In this study, we examined the effect of different fractions and components of Chaga mushroom (Inonotus Obliquus) on viability and apoptosis of colon cancer cells. Among them, one component showed the most effective growth inhibition and was identified as ergosterol peroxide by NMR analysis. We investigated the anti-proliferative and apoptosis mechanisms of ergosterol peroxide associated with its anti-cancer activities in human colorectal cancer (CRC) cell lines and tested its anti-tumor effect on colitis-induced CRC developed by Azoxymethane (AOM)/Dextran sulfate sodium (DSS) in a mouse model. Materials and methods We used MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays, flow cytometry assays, Western blot analysis, colony formation assays, reverse transcription-polymerase chain reaction (RT-PCR), immunohistochemistry (IHC), and AOM/DSS mouse models to study the molecular mechanism of metastatic activities in CRC cells. Results Ergosterol peroxide inhibited cell proliferation and also suppressed clonogenic colony formation in HCT116, HT-29, SW620 and DLD-1 CRC cell lines. The growth inhibition observed in these CRC cell lines was the result of apoptosis, which was confirmed by FACS analysis and Western blotting. Ergosterol peroxide inhibited the nuclear levels of β-catenin, which ultimately resulted in reduced transcription of c-Myc, cyclin D1, and CDK-8. Ergosterol peroxide administration showed a tendency to suppress tumor growth in the colon of AOM/DSS-treated mice, and quantification of the IHC staining showed a dramatic decrease in the Ki67-positive staining and an increase in the TUNEL staining of colonic epithelial cells in AOM/DSS-treated mice by ergosterol peroxide for both prevention and therapy. Conclusion Our data suggest that ergosterol peroxide suppresses the proliferation of CRC cell lines and effectively inhibits colitis-associated colon cancer in AOM/DSS-treated mice. Ergosterol peroxide down-regulated β-catenin signaling, which exerted anti-proliferative and pro-apoptotic activities in CRC cells. These properties of ergosterol peroxide advocate its use as a supplement in colon cancer chemoprevention. [ABSTRACT FROM AUTHOR]

An increasing importance of chemoprevention for controlling cancer risks prompted the discovery of new active cancer chemopreventive agents. In this study, we designed and synthesized substituted hexa-2,4-diyne-1,6-diols, more structurally simplified, tunable, and easily preparable than natural gymnasterkoreaynes, and evaluated their cancer chemopreventive activities by measuring concentration of doubling quinone reductase activity (CD), cell viability, and chemopreventive index (CI). Most of the diols exhibited good CD activity and low cytotoxicity. In particular, tetradeca-5,7-diyne-4,9-diol and 2-methyltetradeca-5,7-diyne-4,9-diol showed the best cancer chemopreventive activity, approximately equipotent to that of sulforaphane. And, by synthesizing optically active stereoisomers of selected active compounds, the effect of stereochemistry was also studied. Eventually, we produced a chemopreventive compound for in vivo study. [ABSTRACT FROM AUTHOR]

Coenzyme Q10 (CoQ10) is a lipid-soluble antioxidant synthesized in human body. This enzyme promotes immune system function and can be used as a dietary supplement. Rheumatoid arthritis (RA) is an autoimmune disease leading to chronic joint inflammation. RA results in severe destruction of cartilage and disability. This study aimed to investigate the effect of CoQ10 on inflammation and Th17 cell proliferation on an experimental rheumatoid arthritis (RA) mice model. CoQ10 or cotton seed oil as control was orally administrated once a day for seven weeks to mice with zymosan-induced arthritis (ZIA). Histological analysis of the joints was conducted using immunohistochemistry. Germinal center (GC) B cells, Th17 cells and Treg cells of the spleen tissue were examined by confocal microscopy staining. mRNA expression was measured by real-time PCR and protein levels were estimated by enzyme-linked immunosorbent assay (ELISA). Flow cytometric analysis (FACS) was used to evaluate Th17 cells and Treg cells. CoQ10 mitigated the severity of ZIA and decreased serum immunoglobulin concentrations. CoQ10 also reduced RANKL-induced osteoclastogenesis, inflammatory mediators and oxidant factors. Th17/Treg axis was reciprocally controlled by CoQ10 treatment. Moreover, CoQ10 treatment on normal mouse and human cells cultured in Th17 conditions decreased the number of Th17 cells and enhanced the number of Treg cells. CoQ10 alleviates arthritis in mice with ZIA declining inflammation, Th17 cells and osteoclast differentiation. These findings suggest that CoQ10 can be a potential therapeutic substance for RA. [ABSTRACT FROM AUTHOR]

Arylnaphthalene lactones, which are natural lignans and isolated from a wide range of plants, exhibit significant biological activity, including anticancer and antiviral activities. In this work, we have developed a versatile and convergent synthetic method for arylnaphthalene lactones, which involves the use of benzoin condensation and thermal intramolecular cyclization for preparing the key intermediate, naphthol. A high-yielding Suzuki reaction is utilized to introduce the aryl group to the C9 position of the naphthalene lactones, which allows for the construction of the arylnaphthalene lactone skeleton. [ABSTRACT FROM AUTHOR]

Abstract: Next-generation sequencing (NGS) technologies recently developed are now used for study of genomes from various organisms. Sequencing-by-synthesis (SBS) is a key strategy in the NGS. The SBS uses nucleotides so-called dual-modified reversible terminators (DRTs) in which bases are labeled with fluorophores and 3′-OH is protected with a reversibly cleavable chemical group, respectively. In this study, we examined the possibility of performing SBS with mono-modified reversible terminators (MRTs), in which the reversible blocking group on the 3′-OH plays a dual role as a fluorescent signal report as well as a chemical protection. We studied cyclic reversible termination by using two MRTs (dA and dT), wherein the modifications were two different fluorophores and cleavable to regenerate a free 3′-OH. We here demonstrated that SBS could be achieved with incorporation of MRTs by a DNA polymerase and correct base-calls based on the two different colors from the fluorophores. [Copyright &y& Elsevier]

Highlights: [•] Type I and Type II of arylnaphthalene lactones were synthesized regioselectively. [•] Arylalkene–arylalkynes were used in the intramolecular Diels–Alder reaction. [•] Dihydronaphthalene lactones were converted to arylnaphthalene lactones by DDQ. [•] We report the synthesis of Type I taiwanin C, daurinol, and Type II justidicin E. [Copyright &y& Elsevier]

Abstract: Novel and unusual dimerization reaction of α-chloroacetoacetanilide under basic reaction condition to give structurally unique 6-oxa-3-azabicyclo[3.1.0]hexane was described. [Copyright &y& Elsevier]