Phenothiazine-, Dihydroacridine-, and Acridone-Based Boron Difluoride Complexes: Synthesis and Structure-Property Relationships.

Boron difluoride complexes of phenothiazine, 9,10-dihydroacridine, and acridone derivatives with a pyridyl group were synthesized. Their structures, dynamic conformational behaviors, and photophysical properties, including solid-state fluorescence, were disclosed. The effects of the oxidation state of the sulfur atom in the phenothiazine derivatives on their properties were also clarified.

A series of boron difluoride complexes of azinylcarbazoles: synthesis and structure-property relationships.

A series of boron difluoride (BF2) complexes of azinylcarbazoles 1b-1h were synthesized, and the effects of the structure of azine moieties on the photophysical and electrochemical properties of the BF2 complexes were clarified. UV-vis analysis of 1b with quinoline, 1c with isoquinoline, and fully fused 1d revealed that fusion with a benzene ring to a pyridylcarbazole BF2 complex (1a) resulted in red shifts of longest-maximum absorption wavelengths (λmax). UV-vis analysis of 1e and 1f with pyrimidine, 1g with pyridazine, and 1h with pyrazine revealed that substitution of a carbon atom to a nitrogen atom in 1a also resulted in red shifts of λmax. The fluorescence quantum yields (Φf) decreased from 1a to 1b-1h, and especially, the fluorescence of 1e, 1g, and 1h was quenched in solution. At 77 K, the emission intensities of 1b-1h were significantly increased compared with those at ambient temperature, and they also exhibited phosphorescence with relatively narrow energy gaps between the singlet and triplet excited states. These results on the emission at 77 K indicate that the quench of fluorescence from 1e, 1g, and 1h at ambient temperature originates from both internal conversions and intersystem crossing. In the solid state, all of the complexes including 1e, 1g, and 1h exhibited emission. Distinctive aggregation-induced emission properties were observed for 1e-1h. Electrochemical measurements revealed that the replacement of the pyridine moiety in 1a with azine moieties reduced electrochemical gaps mainly due to a decrease in the LUMO levels. The effects of azine moieties on electronic structures were also discussed based on theoretical calculations.

Serum periostin levels in adolescents.

BACKGROUND: The significance of periostin as a biomarker of Th2-induced airway inflammation has recently been highlighted in adult patients with allergic diseases. It may help identify drug-responsive inflammatory phenotypes, particularly in children. However, little is known about the usefulness of this parameter as a biomarker for allergic diseases in children. Furthermore, it is not known how much adolescent bone metabolism affects allergic inflammation. OBJECTIVE: To evaluate the relationship between serum periostin levels and allergic diseases in adolescents, we investigated periostin levels and the prevalence of allergic diseases. METHODS: We conducted a cross-sectional observational study of 100 males and females in two age groups: age 9-12 years (pre-early adolescence) and 13-15 years (post-early adolescence). Serum periostin levels were determined using Enzyme-Linked Immuno Sorbent Assay (ELISA). Presence of allergic diseases and allergy sensitization were obtained via a self-reported survey and the Multiple Antigen Simultaneous Test (MAST). The protocol was registered in a clinical trial registry as UMIN 000036051. RESULTS: There were no significant differences in serum periostin levels between pre-early and post-early adolescents. There were no differences by gender. Age and Body Mass Index were not significantly associated with serum periostin levels. Periostin levels were elevated in adolescents with allergic diseases overall compared to healthy adolescents [mean (95%CI): 41.6 (33.4, 49.7) vs. 28.6 (21.9, 35.3) ng/ml; P < 0.05]. CONCLUSIONS: The effects of bone metabolism on serum periostin levels may be limited at 9-15 years of age. Further studies are required to determine reference values in adolescents.

Effect of fexofenadine/pseudoephedrine combination tablet on nasal obstruction in patients with allergic rhinitis using rhinomanometry: A randomized controlled trial.

BACKGROUND: A fexofenadine/pseudoephedrine combination tablet (F/P) is an optimal product for nasal obstruction. It contains fexofenadine hydrochloride, a histamine H1-receptor antagonist for sneezing and rhinorrhea and pseudoephedrine hydrochloride, an α-adrenergic agonist. The effect of an antihistamine-decongestant on nasal obstruction has been demonstrated in previous studies, but onset of action and efficacy data on nasal obstruction are limited. OBJECTIVE: We estimated the efficacy of F/P on nasal obstruction in patients with house dust mite-induced allergic rhinitis (AR) versus fexofenadine (F) using objective methods. METHODS: In this single-center, single-dose, prospective, randomized, parallel-group study, 24 adult patients with a history of at least 2 years of AR and nasal obstruction were randomized to receive F/P or F. The effect on nasal obstruction was evaluated using nasal airflow and visual analog scale (VAS) score measured at 30-minute intervals before and for 8 hours after dosing. The primary end point was onset of action, based on a comparison of absolute change from baseline in nasal airflow between F/P and F. The protocol was registered in a clinical trial registry as UMIN 000041845. RESULTS: The onset of action for F/P was 30 minutes based on nasal airflow and 60 minutes based on VAS. F/P maintained a significant beneficial effect after onset of effect, while F showed no significant change during the test period. CONCLUSIONS: We found F/P had a clear effect on nasal obstruction associated with perennial AR when compared with F. There was a time lag in nasal airflow improvement and nasal obstruction relief.

Monoradicals and Diradicals of Dibenzofluoreno[3,2-b]fluorene Isomers: Mechanisms of Electronic Delocalization.

The preparation of a series of dibenzo- and tetrabenzo-fused fluoreno[3,2-b]fluorenes is disclosed, and the diradicaloid properties of these molecules are compared with those of a similar, previously reported series of anthracene-based diradicaloids. Insights on the diradical mode of delocalization tuning by constitutional isomerism of the external naphthalenes has been explored by means of the physical approach (dissection of the electronic properties in terms of electronic repulsion and transfer integral) of diradicals. This study has also been extended to the redox species of the two series of compounds and found that the radical cations have the same stabilization mode by delocalization that the neutral diradicals while the radical anions, contrarily, are stabilized by aromatization of the central core. The synthesis of the fluorenofluorene series and their characterization by electronic absorption and vibrational Raman spectroscopies, X-ray diffraction, SQUID measurements, electrochemistry, in situ UV-vis-NIR absorption spectroelectrochemistry, and theoretical calculations are presented. This work attempts to unify the properties of different series of diradicaloids in a common argument as well as the properties of the carbocations and carbanions derived from them.

Visualization of Lipid Droplets in Living Cells and Fatty Livers of Mice Based on the Fluorescence of π-Extended Coumarin Using Fluorescence Lifetime Imaging Microscopy.

Lipid droplets (LDs) are closely related to lipid metabolism in living cells and are highly associated with diverse diseases such as fatty liver, diabetes, and cancer. Herein we describe a π-extended fluorescent coumarin (PC6S) for visualizing LDs in living cells and in the tissues of living mice using confocal fluorescence lifetime imaging microscopy (FLIM). PC6S showed a large positive solvatochromic shift and high fluorescence quantum yield (>0.80) in both nonpolar and polar solvents. Additionally, the fluorescence lifetimes of PC6S were largely dependent on solvent polarity. The excellent spectral and photophysical properties of PC6S allowed its selective staining of LDs in living and fixed cells, and multicolor imaging. Fluorescence lifetime measurements of PC6S allowed estimation of the apparent polarity of LDs. The high photostability and long intracellular retention of PC6S supported in situ visualization of the formation processes of LDs resulting from the accumulation of fatty acid. Furthermore, intravenous administration of PC6S and use of the FLIM system allowed the imaging of LDs in hepatocytes in living normal mice and the growth of LDs resulting from the excess accumulation of lipids in high-fat-diet-fed mice (fatty liver model mice). Taking advantage of the high selectivity and sensitivity of PC6S for LDs in liver, we could visualize the adipocytes of lipid-rich tissues and LDs in kidney peritubular cells by PC6S fluorescence. These results demonstrated that PC6S combined with a FLIM system can be useful for monitoring and tracking the formation of LDs in both cultured cells and specific tissues and organs.

Chemical transformations of push-pull fluorenones: push-pull dibenzodicyanofulvenes as well as fluorenone- and dibenzodicyanofulvene-tetracyanobutadiene conjugates.

Push-pull fluorenones (FOs) were synthesized by treating a benzopentalenequinone (BPO) derivative with alkynes that bear an electron-rich aniline moiety via a regioselective [4 + 2] cycloaddition (CA) followed by a [4 + 1] retrocycloaddition (RCA). The resulting FOs were readily converted into dibenzodicyanofulvenes (DBDCFs) by treatment with malononitrile in the presence of TiCl4 and pyridine. The FOs and DBDCFs exhibit intramolecular charge-transfer (ICT) that manifests in absorptions at 350-650 nm and amphoteric electrochemical behavior. Furthermore, FOs and DBDCFs that contain a C[triple bond, length as m-dash]C bond react with tetracyanoethylene in a formal [2 + 2] CA followed by a retro-electrocyclization to afford sterically congested tetracyanobutadiene (TCBD) conjugates. The substituent (H or Me) on the aromatic ring adjacent to the butadiene moiety thereby determines whether the butadiene adopts an s-cis or s-trans conformation, and thus controls the physicochemical properties of the resulting TCBDs. The TCBD conjugates exhibit ICT absorptions (≤800 nm) together with up to four reversible reduction steps.

Trithiazolyl-1,3,5-triazines bearing decyloxybenzene moieties: synthesis, photophysical and electrochemical properties, and self-assembly behavior.

We report the synthesis, photophysical properties, redox characteristics, and self-assembly behavior of disk-shaped trithiazolyl-1,3,5-triazines that bear decyloxybenzene moieties. These compounds were synthesized by a Migita-Kosugi-Stille coupling reaction of 1,3,5-trichlorotriazine with three different tributyltin(thiazoles) as the key step. The structure-property relationships, namely the effects of the incorporation of thiazole units into the triazine unit, the conjugation connectivity between the thiazole and triazine units, and the insertion of ethynylene spacers between the thiazole and decyloxybenzene moieties on the properties of the trithiazolyl-1,3,5-triazines were comprehensively investigated. Binding of the triazine core at the 5-position of the thiazole moieties effectively extended the π-conjugation and afforded high fluorescence quantum yields. The ethynylene spacers substantially lowered the LUMO level relative to the HOMO level. The prepared trithiazolyl-1,3,5-triazines self-assembled in solution, and the introduction of thiazole units at the 5-position enhanced this behavior. Detailed thermodynamic studies on the self-association behavior were conducted, and the formation of self-assembled 1D clusters is disclosed.

Tetraalkoxyphenanthrene-Fused Thiadiazoloquinoxalines: Synthesis, Electronic, Optical, and Electrochemical Properties, and Self-Assembly.

π-Extended thiadiazoloquinoxaline (TQ) derivatives 1a,b-3a,b, in which a tetraalkoxyphenanthrene moiety is annulated with the TQ core and benzene rings are incorporated via the ethynylene spacer, were synthesized. They display absorption bands reaching into 750 nm and possess the electron-affinity comparable to [60]fullerene. The CF3- and OMe-substituents on the benzene rings have moderate effects on modulation of the HOMO and LUMO levels. Tetraalkoxyphenanthrene-fused TQs 1a,b-3a,b aggregate in the solid state and assemble in solution through π-π stacking interactions. The self-assembly of 1a,b-3a,b into 1D superstructures was confirmed, and the difference in the alkoxy groups and the solvents for self-assembly proved to change their morphology. Comparison of the properties of 1a and those of reference compounds 4 and 5 clarified the effects of both the fusion of the phenanthrene moiety and the introduction of ethynylene spacers on the properties.

Tetraalkoxyphenanthrene-Fused Hexadecadehydro[20]- and Tetracosadehydro[30]annulenes: Syntheses, Aromaticity/Antiaromaticity, Electronic Properties, and Self-Assembly.

Tetraalkoxyphenanthrene-fused hexadecadehydro[20]- and tetracosadehydro[30]annulenes possessing octatetrayne linkages were synthesized and their properties together with those of phenanthrene-fused octadehydro[12]- and dodecadehydro[18]annulenes have been investigated. Various spectroscopic and electrochemical measurements as well as quantum chemical calculations support that planar [20]- and [30]annulenes are weakly antiaromatic and nonaromatic, respectively. The detailed concentration- and temperature-dependent 1H NMR and UV-vis data of present dehydroannulenes provided evidence for the enhancement of π-π stacking interactions by extension of the acetylenic linkages. Dehydroannulenes formed self-assembled clusters and their morphology and crystallinity proved to depend on the length of acetylenic linkages, the shape of dehydroannulene core, and the bulkiness of alkoxy groups appended to the phenanthrene moieties.

Blue Fluorescence from BF2 Complexes of N,O-Benzamide Ligands: Synthesis, Structure, and Photophysical Properties.

Small molecules having intense luminescence properties are required to promote biological and organic material applications. We prepared five types of benzamides having pyridine, pyridazine, pyrazine, and pyrimidine rings and successfully converted them into three types of the difluoroboronated complexes, Py@BAs, as novel blue fluorophores. Py@BA having a pyridine moiety (2-Py@BA) showed no fluorescence in solution, whereas Py@BAs of pyridazine and pyrazine moieties (2,3-Py@BA and 2,5-Py@BA, respectively) emitted blue fluorescence with quantum yields of ca. 0.1. Transient absorption measurements using laser flash photolysis of the Py@BAs revealed the triplet formation of 2,3- and 2,5-Py@BAs, while little transient signal was observed for 2-Py@BA. Therefore, the deactivation processes from the lowest excited singlet state of fluorescent 2,3- and 2,5-Py@BAs consist of fluorescence and intersystem crossing to the triplet state while that of the nonfluorescent Py@BA is governed almost entirely by internal conversion to the ground state. Conversely, in the solid state, 2-Py@BA emitted intense fluorescence with a fluorescence quantum yield as high as 0.66, whereas 2,3- and 2,5-Py@BAs showed fluorescence with quantum yields of ca. 0.2. The crystal structure of 2-Py@BA took a herringbone packing motif, whereas those for 2,3- and 2,5-Py@BAs were two-dimensional sheetlike. On the basis of the difference in crystal structures, the emission mechanism in the solid state was discussed.

Benzo- and Naphthopentalenes: Syntheses, Structures, and Properties.

Benzo- and naphthopentalene derivatives were synthesized, and the effects of structural variations on their antiaromaticity and optoelectronic and electrochemical properties were examined experimentally and theoretically in detail. The results unveiled that with increasing the bond order of the carbon-carbon bond ([5,6] junction) shared by the pentalene and aromatic moieties, the 8π antiaromatic character of pentalene is enhanced and the HOMO-LUMO gap is decreased, which accompanies both the elevation of the HOMO level and the lowering of the LUMO level. The ethynylene units between the pentalene skeleton and the phenyl groups proved to extend π-conjugation sufficiently.

Photochemical synthesis and photophysical features of ethynylphenanthrenes studied by emission and transient absorption measurements.

Phenanthrenes substituted with trimethylsilylethynyl and phenylethynyl groups were photochemically prepared, and their photophysical properties were systematically investigated based on measurements of fluorescence quantum yields, lifetimes, and transient absorption. Introducing ethynyl groups into the phenanthrene skeleton caused an increase in the fluorescence quantum yields compared to that of phenanthrene. The quantum yields and rates of fluorescence were dependent on the substituting position(s) and the terminating group for the C-C triple bond. The observation of the triplet-triplet absorption of the substituted phenanthrenes was evident for the nonradiative process being intersystem crossing competitive with the fluorescence process. The mechanism of increasing the fluorescence abilities by substituting with the ethynyl group(s) was discussed with the aid of TD-DFT calculations.

Effects of cataracts on flicker electroretinograms recorded with RETeval™ system: new mydriasis-free ERG device.

BACKGROUND: The purpose of this study was to evaluate the effects of cataracts on the flicker electroretinograms (ERGs) recorded with the RETeval™ system under mydriatic-free conditions. METHODS: This was a retrospective study of 82 eyes of 60 patients with cataracts and 52 eyes of 38 patients who were pseudophakic. Flicker ERGs were recorded with the RETeval™ system (LKC Technologies, Gaithersburg, MD) under mydriatic-free condition with skin electrodes. Flicker ERGs were elicited by white light delivered at a frequency of 28.3 Hz and intensity of 8 Td-s. The implicit times and amplitudes of the ERGs recorded from the Grade 2 cataract, Grade 3 cataract, and pseudophakic groups were compared. RESULTS: The mean amplitude was significantly smaller in both cataract groups than the pseudophakic group (Grade 2 cataract vs pseudophakic group, P < 0.0001; Grade 3 cataract vs pseudophakic group, P < 0.0001; Grade 2 cataract vs Grade 3 cataract, P = 0.027). The mean implicit times was significantly longer in both cataract groups than the pseudophakic group (Grade 2 cataract vs pseudophakic group, P = 0.046; Grade 3 cataract vs pseudophakic group, P = 0.0004; Grade 2 cataract vs Grade 3 cataract, P = 0.0084). CONCLUSIONS: The results indicate that the presence of Grade 2 or more cataracts will affect both the amplitude and the implicit time of the flicker ERGs. The presence of cataracts should be taken into consideration when interpreting the flicker ERG recorded with RETeval™.

A series of π-extended thiadiazoles fused with electron-donating heteroaromatic moieties: synthesis, properties, and polymorphic crystals.

π-Extended thiadiazoles 4-8 fused with various electron-donating heteroaromatic moieties have been designed and synthesized. Just like thiadiazoles 1-3 synthesized previously, 4-8 exhibit intramolecular charge-transfer (CT) interactions, moderate-to-good fluorescence quantum yields of up to 0.78, and electrochemical amphoterism. In comparison with 1-3, the benzannulation in thiadiazoles 4-7 moderately extends the π conjugation and significantly increases the stability of the cationic species formed upon electrochemical oxidation. The fluorescence quantum yields increase remarkably from 3 to 6 and 7 due to the efficient suppression of nonradiative intersystem crossing resulting from the benzannulation. The properties of 4-8 strongly reflect the different species annulated to the pyrrole rings, namely benzothiophene, naphthalene, and benzofuran. Eleven crystals, including poly- and pseudopolymorphic crystals of 1 (1-Crys.(Y) and 1-Crys.(G)), 2 (2-Crys.(O) and 2-Crys.(G)), 4 (4-Crys.(O) and 4-Crys.(G)), and 6 (6-Crys.(O) and 6-Crys.(G)), were obtained and characterized by X-ray crystallography. The fluorescence colors and efficiencies are distinct for each poly- and pseudopolymorph of 1, 2, 4, and 6. It has been suggested that both the extent of the electronic interactions in the π-stacked dimers and the presence of excitonic interactions originating in the 1D face-to-face slipped columns affect the fluorescence wavelengths of the poly- and pseudopolymorphs.

Series of Carbazole-Pyrimidine Conjugates: Syntheses and Electronic, Photophysical, and Electrochemical Properties.

A series of carbazole-pyrimidine conjugates 1-17 were synthesized by Pd-catalyzed cross-coupling, oxidation, and nucleophilic aromatic substitution reactions. In 1-17, the carbazole moieties are connected at the 4,6-positions of the pyrimidine ring either directly or via ethynylene or vinylene spacers, and various electron-donating or electron-withdrawing substituents are introduced at the 2-position of the pyrimidine ring. The effects of structural variations on the electronic, photophysical, and electrochemical properties of 1-17 were comprehensively investigated. Compounds 1-17 exhibit intramolecular charge-transfer (ICT) states, which essentially lead to moderate-to-strong fluorescence emission with large Stokes shifts depending on the solvent polarity. These compounds tend to show significant changes in optical and fluorescence properties upon addition of trifluoroacetic acid. The electron-accepting ability of these compounds can be tuned by both substituents on the pyrimidine moiety and spacers. The ethynylene spacer lowers both the HOMO and LUMO levels, while the vinylene spacer elevates the HOMO level and lowers the LUMO level. The X-ray crystal structures of 3, 6, 11, and 14 are also disclosed.

Systematic structure-property investigations on a series of alternating carbazole-thiophene oligomers.

A series of alternating carbazole-thiophene oligomers, namely 2,7-linked carbazole-thiophene oligomers 1, 3, 5, 7, and 9 and 3,6-linked ones 2, 4, 6, 8, and 10, in which the molecular length was systematically elongated, were synthesized by Suzuki-Miyaura coupling reactions. The effects of the conjugation connectivity between the carbazole and thiophene moieties and the molecular length on the electronic, photophysical, and electrochemical properties of 1-10 were comprehensively investigated. In the present oligomer architectures, the connection with thiophene at the 2,7-positions of carbazole ensures π-conjugation to a high extent and high fluorescence quantum yields, while that at the 3,6-positions enhances the donor ability. The increase in the molecular length of the 2,7-linked oligomers effectively extends π-conjugation. The relationship between structural variations and photophysical properties was examined by fluorescence lifetime measurements in detail. The X-ray crystal structure of 6 was also disclosed.

[The Roles of Aß in Alzheimer's Disease: In Light of the Latest Findings].

The 'amyloid hypothesis', initially put forward in 1992, posits that amyloid ß protein (Aß) contributes to neurodegeneration through aberrant aggregation. In the process of this aberrant aggregation, Aß forms oligomers, protofibrils, and mature fibrils, ultimately developing plaques. These mature fibrils and plaques were believed to be the culprits behind the neurotoxicity and neurodegeneration seen in Alzheimer's disease (AD). However, growing evidence in recent years has led to the 'Aß oligomer hypothesis', which suggests that the intermediate forms of aggregates, such as oligomers and protofibrils, exhibit stronger neurotoxicity than the mature forms. Consequently, efforts have been made to develop anti-Aß antibody drugs that specifically target these intermediate aggregates. Such interventions hold promise as disease-modifying treatments for AD.

[Mechanism of action and clinical trial results of Lecanemab (Leqembi® 200†|mg, 500†|mg for Intravenous Infusion), a novel treatment for Alzheimer's disease].

Lecanemab is a humanized monoclonal antibody directed against human soluble amyloid-ß aggregates. It was developed for the treatment of early Alzheimer's disease (mild cognitive impairment or mild dementia stage of Alzheimer's disease). Among the amyloid-ß (Aß) involved in Alzheimer's disease, Lecanemab selectively binds to the highly neurotoxic Aß protofibrils, and is thought to reduce Aß protofibrils and amyloid plaques (Aß plaques) in the brain. The efficacy and safety of Lecanemab in early Alzheimer's disease were investigated in an international Phase II placebo-controlled study (Study 201) and an international Phase III placebo-controlled study (Study 301). Both studies included Japanese subjects. Lecanemab was given accelerated approval in the United States in January 2023, followed by traditional approval in July 2023. In Japan, it was approved for "control of the progression of mild cognitive impairment or mild dementia stage of Alzheimer's disease" in September 2023, and was added to the NHI drug price list in December 2023.

Combination Biologic Therapy with Mepolizumab and Dupilumab for Severe Eosinophilic Granulomatosis with Polyangiitis and Chronic Rhinosinusitis with Nasal Polyp.

We report the case of a 55-year-old female with eosinophilic granulomatosis with polyangiitis and chronic rhinosinusitis with nasal polyp. Rhinosinusitis recurred 6 months after full-house endoscopic sinus surgery. Although conventional treatment with azathioprine and mepolizumab with steroids was given, it was difficult to simultaneously control both rhinosinusitis and eosinophilic granulomatosis with polyangiitis. Clinical examinations showed polyps in the olfactory cleft, and the patient's anosmia gradually became persistent. Even after administering mepolizumab for a certain period of time, symptoms did not improve, but when the biologic agent was switched to dupilumab, an improvement in recalcitrant chronic rhinosinusitis with nasal polyp was observed. While dupilumab was administered intermittently for refractory chronic rhinosinusitis with nasal polyp, the rhinosinusitis improved and symptoms such as worsening of eosinophilic granulomatosis with polyangiitis paresthesia were observed. Both symptoms gradually subsided 19 months after starting intermittent administration, leading to the discontinuation of dupilumab administration. Rhinosinusitis in the setting of eosinophilic granulomatosis with polyangiitis may be refractory in some cases, and this case provides findings demonstrating the strong effect of dupilumab on eosinophilic inflammation.