Hexagonal Prismatic Siloxanes Functionalized with Organosilyl Groups as Building Blocks of Nanoporous Materials.

Utilization of well-defined siloxane molecules allows for the construction of functional siloxane-based nanoporous materials based on the molecular design. Herein, a novel class of siloxane-based porous materials is synthesized via cross-linking of dimethylsilyl- and dimethylvinylsilyl-functionalized cage siloxanes with double-6-ring (D6R) geometry. Compared with the conventional double-4-ring cage siloxane, this study highlights the characteristics of D6R siloxanes as building blocks, demonstrating their high surface area and chemical stability. Furthermore, density functional theory calculations show their unique cation encapsulation ability.

Gold-catalyzed dual C-C bond cleavage of biphenylenes bearing a pendant alkyne at ambient temperature.

We report a catalytic skeletal rearrangement of biphenylenes with a pendant alkyne moiety at room temperature by a cationic gold catalyst, which involves the cleavage of two bonds: the C-C bond of biphenylene and the C(sp)-C(sp2 or sp3) bond. Experimental and theoretical studies revealed that the reaction mechanism included π-activation of the alkyne, ring expansion and 1,2-carbon shift.

Identification of Antiglycative Compounds in Japanese Red Water Pepper (Red Leaf Variant of the Persicaria hydropiper Sprout).

Glycation, the nonenzymatic reaction between proteins and excess blood sugar, is implicated in multiple disorders and occurs via the formation and accumulation of advanced glycation end products (AGEs). In our previous studies, we demonstrated that the red-leaf variant of the Persicaria hydropiper sprout (Japanese red water pepper, Benitade) is one of the potent plants that inhibit formation of AGEs. In this study, we aimed to identify antiglycative compounds in Benitade. Benitade extracts were prepared with hot water, then fractionated by using high-performance liquid chromatography (HPLC). The antiglycative efficacy of each fraction was evaluated by measuring the formation of fluorescent AGEs (Ex 370 nm/Em 440 nm). Two fractions, which contained peaks at 26.4 min and 31.8 min, showed potent antiglycative efficacy. When we hydrolyzed these peaks, they shifted to 32.5 and 41.4 min, which are the same retention times as cyanidin and quercetin, respectively. Based on thin-layer chromatography, both compounds contained galactose. Finally, ultrahigh-performance liquid chromatography/quadrupole-time of flight mass spectrometry (UHPLC-QqTOF-MS) analyses were performed to determine the structure of those compounds. Overall, we identified two glycosides, cyanidin 3-O-galactoside (idaein) and quercetin 3-O-galactoside (hyperin), as representative antiglycative compounds in Benitade.

Nudged elastic band method and density functional theory calculation for finding a local minimum energy pathway of p-benzoquinone and phenol fragmentation in mass spectrometry.

Analysis of the fragmentation pathways of molecules in mass spectrometry gives a fundamental insight into gas-phase ion chemistry. However, the conventional intrinsic reaction coordinates method requires knowledge of the transition states of ion structures in the fragmentation pathways. Herein, we use the nudged elastic band method, using only the initial and final state ion structures in the fragmentation pathways, and report the advantages and limitations of the method. We found a minimum energy path of p-benzoquinone ion fragmentation with two saddle points and one intermediate structure. The primary energy barrier, which corresponded to the cleavage of the C-C bond adjacent to the CO group, was calculated to be 1.50 eV. An additional energy barrier, which corresponded to the cleavage of the CO group, was calculated to be 0.68 eV. We also found an energy barrier of 3.00 eV, which was the rate determining step of the keto-enol tautomerization in CO elimination from the molecular ion of phenol. The nudged elastic band method allowed the determination of a minimum energy path using only the initial and final state ion structures in the fragmentation pathways, and it provided faster than the conventional intrinsic reaction coordinates method. In addition, this method was found to be effective in the analysis of the charge structures of the molecules during the fragmentation in mass spectrometry.

Observed adducts on positive mode direct analysis in real time mass spectrometry - Proton/ammonium adduct selectivities of 600-sample in-house chemical library.

In this study, direct analysis in real time adduct selectivities of a 558 in-house high-resolution mass spectrometry sample library was evaluated. The protonated molecular ion ([M + H]+) was detected in 462 samples. The ammonium adduct ion ([M + NH4]+) was also detected in 262 samples. [M + H]+ and [M + NH4]+ molecular ions were observed simultaneously in 166 samples. These adduct selectivities were related to the elemental compositions of the sample compounds. [M + NH4]+ selectivity correlated with the number of oxygen atom(s), whereas [M + H]+ selectivity correlated with the number of nitrogen atom(s) in the elemental compositions. For compounds including a nitrogen atom and an oxygen atom [M + H]+ was detected; [M + NH4]+ was detected for compounds including an oxygen atom only. Density functional theory calculations were performed for selected library samples and model compounds. Energy differences were observed between compounds detected as [M + H]+ and [M + NH4]+, and between compounds including a nitrogen atom and an oxygen atom in their elemental compositions. The results suggested that the presence of oxygen atoms stabilizes [M + NH4]+, but not every oxygen atom has enough energy for detection of [M + NH4]+. It was concluded that the nitrogen atom(s) and oxygen atom(s) in the elemental compositions play important roles in the adduct formation in direct analysis in real time mass spectrometry.

Stabilizers of edaravone aqueous solution and their action mechanisms. 1. Sodium bisulfite.

Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) has been used as a free radical scavenging drug for the treatment of acute ischemic stroke in Japan since 2001. Edaravone is given to patients intravenously; therefore, it is distributed in the form of an aqueous solution. However, aqueous solutions of edaravone are very unstable because it is present as edaravone anion, which is capable of transferring an electron to free radicals including oxygen, and becomes edaravone radical. We observed the formation of hydrogen peroxide and edaravone trimer when aqueous edaravone solution was kept at 60°C for 4 weeks. We proposed the mechanism of edaravone trimer formation from edaravone radicals. Lowering the pH and deoxygenation can effectively increase the stability of aqueous edaravone solution, since the former reduces edaravone anion concentration and the latter inhibits edaravone radical formation. Addition of sodium bisulfite partially stabilized aqueous edaravone solutions and partially inhibited the formation of edaravone trimer. Formation of bisulfite adduct was suggested by 13C NMR and HPLC studies. Therefore, the stabilizing effect of sodium bisulfite is ascribed to the formation of a bisulfite adduct of edaravone and, consequently, reduction in the concentration of edaravone anion.

Prediction of adducts on positive mode electrospray ionization mass spectrometry: proton/sodium selectivity in methanol solutions.

We used positive mode electrospray ionization (ESI) mass spectrometry to examine 540 in-house high-resolution mass spectrometry (HRMS) samples that formed an adducted positive ion. Of the 540 samples, the sodium adduct ([M+Na]⁺) was detected in 480 samples, and the protonated molecule ([M+H]⁺) was detected in 92 samples; both [M+Na]⁺ and [M+H]⁺ were detected in 32 samples. No other adduct ions were predominant. The selectivities of these adducts were evaluated by a two-dimensional plot using topological polar surface area (tPSA) and molecular weight. Two predominant trends were observed: [M+H]⁺ converged around tPSA (Ų) = 20 and molecular weight = 250, and the selectivity for [M+Na]⁺ correlated with the tPSA value. These observations were found to be related to the elemental composition of the sample compounds. From the results obtained by positive mode ESI mass spectroscopy under our experimental conditions, predominant trends were observed with respect to adduct selectivity: compounds containing oxygen atom(s) form [M+Na]⁺, and compounds containing nitrogen but not oxygen atom(s) form [M+H]². Based on these trends, we developed the "Nitrogen-Oxygen rule" (NO rule) to predict the adduct formed by a given compound on positive mode ESI. This NO rule provides a guideline to estimate elemental composition using ESI-HRMS with methanol as mobile phase.

Nonpolar Water Clusters: Proton Nuclear Magnetic Resonance Spectroscopic Evidence for Transformation from Polar Water to Nonpolar Water Clusters in Liquid State.

The hydrophilic/hydrophobic interactions of water are important in biological and chemical self-assembly phenomena. Water clusters in hydrophobic environments exhibit a unique morphology. Their process of formation and nonpolar properties have been extensively studied, but no direct experimental evidence has been available until now. This study provides spectroscopic evidence for the transformation of water to nonpolar configuration via clustering. Although individual water molecules form hydrogen bonds with the hydroxyl protons of n-hexanol when codissolved in a nonpolar solvent (toluene-d8), the water clusters are comprised solely of hydrogen bonds between water molecules and do not form hydrogen bonds with the hydroxyl protons of n-hexanol. This behavior indicates that the water clusters are nonpolar rather than polar. This study reports the first example of nonpolar water configuration produced via a liquid-state clustering. This property is a common and important interfacial phenomenon of water in chemistry, biology, materials science, geology, and meteorology.

Two States of Water Converge to One State below 215 K.

Anomalies of water have been explained by the two-state water model. In the model, water becomes one state upon supercooling. However, water crystallizes completely below 235 K ("no man's land"). The structural origin of the anomalous of the water is hidden in the "no man's land". To understand the properties of water, the spectroscopic experiment in "Norman's land" is inevitable. Hence, we proposed a new soft-confinement method for standard nuclear magnetic resonance spectroscopy to explore the "no man's land". We found the singularity temperature (215 K) at ambient pressure. Water exists in one state below 215 K. Above 215 K, the two states of water are supercritical states of the liquid-liquid critical point. The current study provides a perspective to determine the liquid-liquid critical point of water existing in a high-pressure condition.

Regioisomer Differentiation of Ring-Substituted Chloromethcathinones and Bromomethcathinones Using Gas Chromatography/Electron Ionization-Triple Quadrupole Energy-Resolved Mass Spectrometry.

Positional isomers o-, m-, and p-chloromethcathinones (CMCs) and m- and p-bromomethcathinones (BMCs) were effectively differentiated using gas chromatography (GC) and energy-resolved mass spectrometry (ERMS) analyses. GC demonstrated that the free bases of CMC and BMC isomers were simultaneously baseline-separated at a slow column heating rate (5 °C/min) using a conventional low-polar capillary column. ERMS showed that the trifluoroacetyl derivatives of the positional isomers differed in mass spectral abundances of both halophenyl and halobenzoyl cations. Moreover, the logarithmic plots of the abundance ratio of the two cations as a function of the collision energy (CE) exhibited marked differences among the isomers at each CE, following the order of ortho < para < meta for CMCs and para < meta for BMCs. The performed theoretical calculations of dissociation energy agreed well with the ERMS measurements. The GC and ERMS methodologies enabled unambiguous and reliable differentiation of CMC and BMC isomers. The developed approach is expected to significantly contribute to the accurate structural identification of new psychoactive substances in forensic, toxicological, and clinical fields.

Identification of CD20 C-terminal deletion mutations associated with loss of CD20 expression in non-Hodgkin's lymphoma.

PURPOSE: Rituximab is commonly incorporated into CD20-positive B-cell lymphoma therapy to improve response and prognosis. With increasing use, resistance to rituximab is a continuing concern, but CD20 mutation as a cause of resistance has not previously been reported. EXPERIMENTAL DESIGN: Freshly collected lymphoma cells from 50 patients with previously untreated or relapsed/resistant non-Hodgkin's B-cell lymphomas (diffuse large B cell, n = 22; follicular, n = 7; mucosa associated lymphoid tissue, n = 16; chronic lymphocytic leukemia, n = 2; small lymphocytic lymphoma, n = 1; lymphoplasmacytic, n = 1; mantle cell lymphoma, n = 1) were assessed for CD20 expression by flow cytometry, and CD20 gene sequencing was done on extracted DNA. RESULTS: CD20 mutations were found in 11 (22.0%) of 50 patients and could be grouped as C-terminal deletion (8.0%), early termination (10.0%), and extracellular domain (2.0%) or transmembrane domain (2.0%) mutations. The mean fluorescence intensity of CD20 on fresh lymphoma cells was significantly lower for the C-terminal deletion mutation [3.26; 95% confidence interval (95% CI), 0.09-6.89] compared with wild type (30.8; 95% CI, 22.4-39.2; P < 0.05). In contrast, early termination mutations did not show significant differences in CD20 expression compared with wild type (19.5; 95% CI, 10.7-28.4; P > 0.05). CONCLUSIONS: It is possible that C-terminal deletion mutations of CD20 may be related to relapse/resistance after rituximab therapy. These mutations should be examined in patients showing progression of disease after partial remission.

An imaging-based rapid evaluation method for complement-dependent cytotoxicity discriminated clinical response to rituximab-containing chemotherapy.

PURPOSE: Rituximab has greatly improved the efficacy of chemotherapy regimens for CD20-positive non-Hodgkin's lymphoma. However, although several mechanisms of action of rituximab have been identified, the exact therapeutic functions of these mechanisms remains to be clarified. In addition, there is no established prognostic marker to predict an individual response. This study verified the validity of ex vivo complement-dependent cytotoxicity (CDC) susceptibility as a predictor of pathologic tumor regression in patients undergoing rituximab-containing chemotherapy and examined whether CDC contributes to the mechanism of action of rituximab. EXPERIMENTAL DESIGN: A rapid assay system was established to evaluate the tumoricidal activity of rituximab using a living cell-imaging technique. We analyzed lymph node biopsies obtained from 234 patients with suspected lymphomas and estimated the association between CDC susceptibility and the response to rituximab-containing chemotherapy in diffuse large B-cell lymphoma and follicular lymphoma. RESULTS: This study revealed that CDC susceptibility of lymphoma cells freshly obtained from patients was strongly associated with response to rituximab-containing chemotherapy in both diffuse large B-cell lymphoma and follicular lymphoma. This correlation was not apparent in cases that received chemotherapy without rituximab. CONCLUSIONS: The system that we have established allows a successful assessment of rituximab-induced CDC and can distinguish cases refractory to rituximab-containing chemotherapy. The association between CDC susceptibility and therapy response suggests that CDC is pivotal in the ability of chemotherapy including rituximab to induce remission.

Supercooled Low-Entropy Water Clusters.

The properties of low-entropy water clusters and small bulk water domains in a hydrophobic solvent over a wide temperature range (235-333 K), including supercooling temperatures, were investigated. 1H nuclear magnetic resonance spectroscopy showed singularity temperatures at ∼300, 250, 235, and 225 K. We proposed a model to understand these singularity temperatures in which the low-entropy water cluster is a locally favored tetrahedral structure (LFTS) and the small bulk water domain contains a mixture of disordered normal-liquid structure (DNLS) and LFTS. The model showed that the LFTS and DNLS populations change with applied temperature. Above ∼300 K, all local water structures become a DNLS. The population of LFTS increases with cooling and becomes dominant below ∼250 K. At ∼225 K, all local water structures converge to LFTS. The phase-transition rate of the low-entropy water clusters and small bulk water domains increases significantly at ∼235 K. The phase transition of the low-entropy water clusters showed primary ice nucleation. Low-entropy water clusters in a hydrophobic solvent are a unique water morphology and a probe material for water investigations.

Encapsulation of Cu nanoparticles in nanovoids of plate-like silica sodalite through interlayer condensation of Cu2+ ion-exchanged layered silicate RUB-15.

The interlayer condensation of layered silicates is a unique method for synthesizing zeolites and is effective for the introduction of metal species into platy zeolite frameworks. Layered silicate RUB-15 is a useful starting material because metal ions can be introduced between the layers and zeolite frameworks (all-silica SOD-type zeolite; silica sodalite) can be formed through interlayer condensation. In this study, Cu ions were intercalated into layered silicate RUB-15, and metal Cu nanoparticles were formed in the nanovoids of silica sodalite by a simple heat treatment in an inert atmosphere. Both interlayer condensation and the reduction of Cu2+ ions were confirmed by in situ XRD analysis performed during the heat treatment. The residual interlayer tetramethylammonium ions played two roles: the control of stacking sequence in the interlayer condensation and the reduction of Cu2+ ions. The formed Cu nanoparticles were stable in air atmosphere because of their confinement in the nanovoids of the sodalite frameworks.

Triboionization: a Novel Ionization Method by Peeling of Cohesive Substances for Mass Spectrometry.

A novel ionization/sampling method termed triboionization was developed. Triboionization is an ionization method that only uses cohesive substances, such as food wrap or sticky tape, and does not require an electrode, electric power supply, heat source, light source, radiation, or gas, unlike most other conventional ambient ionization methods. In this study, the sample compound attached to adhesive tape or plastic wrap was quickly peeled off at a distance of approximately 2 cm from the atmospheric interface of a mass spectrometer. All of the five types of food wrap and 13 types of adhesive tape tested successfully ionized caffeine. Nine out of ten model compounds were detected as the corresponding molecular ions in the positive or negative mode by this ionizing contrivance using an oriented polypropylene adhesive tape. The detected molecular ions were typically protonated molecules or sodium adducts in the positive mode or deprotonated molecules in the negative mode. The elemental compositions of the observed ions were confirmed within 5 ppm by high-resolution mass spectrometry. The triboionization phenomenon was considered to depend on physical and electronic events caused by peeling off a cohesive substance. Triboionization is able to provide a compact ion source using only mechanical mechanisms. Additionally, triboionization allows sticky tape to be used as a convenient sampling device for surface analysis.

Long-lived water clusters in hydrophobic solvents investigated by standard NMR techniques.

Unusual physical characteristics of water can be easier explained and understood if properties of water clusters are revealed. Experimental investigation of water clusters has been reported by highly specialized equipment and/or harsh experimental conditions and has not determined the properties and the formation processes. In the current work, we used standard 1H-NMR as a versatile and facile tool to quantitatively investigate water clusters in the liquid phase under ambient conditions. This approach allows collection of data regarding the formation, long lifetime, stability, and physical properties of water clusters, as a cubic octamer in the liquid phase.

Consecutive HDDA and TDDA reactions of silicon-tethered tetraynes for the synthesis of dibenzosilole-fused polycyclic compounds and their unique reactivity.

Silicon-tethered tetraynes possessing a 1,3-diyne moiety underwent consecutive hexadehydro- and tetradehydro-Diels-Alder reactions to give a series of fused polycyclic aromatic compounds containing a dibenzosilole skeleton. The benzene ring in the product acted as a 1,3-diene and reacted with the active alkyne as well as oxygen to provide [4 + 2] cycloadducts.

Energy-resolved mass spectrometry for differentiation of the fluorine substitution position on the phenyl ring of fluoromethcathinones.

A reliable method for structural analysis is crucial for the forensic investigation of new psychoactive substances (NPSs). Towards this end, mass spectrometry is one of the most efficient and facile methods for the identification of NPSs. However, the differentiation among 2-, 3-, and 4-fluoromethcathinones (o-, m-, and p-FMCs), which are ring-fluorinated positional isomers part of the major class of NPSs referred to as synthetic cathinones, remains a challenge. This is mostly due to their similar retention properties and nearly identical full scan mass spectra, which hinder their identification. In this study, we describe a novel and practical method for differentiating the fluorine substitution position on the phenyl ring of FMCs, based on energy-resolved mass spectrometry (ERMS) using an electron ionization-triple quadrupole mass spectrometer. ERMS measurements showed that the three FMC positional isomers exhibited differences in relative abundances of both the fluorophenyl cation (m/z 95) and the fluorobenzoyl cation (m/z 123). The logarithmic plots of the abundance ratio of these two cations (m/z 95 to m/z 123) as a function of the collision energy (CE) followed the order of o-FMC < p-FMC < m-FMC at each CE, which allowed the three isomers to be unambiguously and reliably differentiated. The theoretical dissociation energy calculations confirmed the relationship obtained by ERMS analyses, and additional ERMS measurements of methylmethcathinone positional isomers showed that the differences in abundance among the FMCs were attributed to the differences in their collision-induced dissociation reactivities arising from the halogen-induced resonance effects on the phenyl ring. Moreover, the method for differentiation described herein was successfully applied to the actual samples containing seized drugs. We expect that the described methodology will also contribute significantly to the reliable and accurate structural identification of NPSs in the fields of therapeutic, clinical, and forensic toxicology.

DFT Studies on the Mechanism of the Iridium-Catalyzed Formal [4 + 1] Cycloaddition of Biphenylene with Alkenes.

Recently, we reported an Ir-catalyzed formal [4 + 1] cycloaddition of biphenylenes with alkenes, which gave 9,9-disubstituted fluorenes in moderate to excellent yields. We proposed a reaction mechanism that involved the intermolecular insertion of alkenes, ß-elimination, and intramolecular insertion based on the results of experimental mechanistic studies. Herein, we further support the proposed mechanism by density functional theory calculations and explain why [4 + 1] cycloaddition proceeds rather than conventional [4 + 2] cycloaddition.

Aggregation Number in Water/n-Hexanol Molecular Clusters Formed in Cyclohexane at Different Water/n-Hexanol/Cyclohexane Compositions Calculated by Titration 1H NMR.

Upon titration of n-hexanol/cyclohexane mixtures of different molar compositions with water, water/n-hexanol clusters are formed in cyclohexane. Here, we develop a new method to estimate the water and n-hexanol aggregation numbers in the clusters that combines integration analysis in one-dimensional 1H NMR spectra, diffusion coefficients calculated by diffusion-ordered NMR spectroscopy, and further application of the Stokes-Einstein equation to calculate the hydrodynamic volume of the clusters. Aggregation numbers of 5-15 molecules of n-hexanol per cluster in the absence of water were observed in the whole range of n-hexanol/cyclohexane molar fractions studied. After saturation with water, aggregation numbers of 6-13 n-hexanol and 0.5-5 water molecules per cluster were found. O-H and O-O atom distances related to hydrogen bonds between donor/acceptor molecules were theoretically calculated using density functional theory. The results show that at low n-hexanol molar fractions, where a robust hydrogen-bond network is held between n-hexanol molecules, addition of water makes the intermolecular O-O atom distance shorter, reinforcing molecular association in the clusters, whereas at high n-hexanol molar fractions, where dipole-dipole interactions dominate, addition of water makes the intermolecular O-O atom distance longer, weakening the cluster structure. This correlates with experimental NMR results, which show an increase in the size and aggregation number in the clusters upon addition of water at low n-hexanol molar fractions, and a decrease of these magnitudes at high n-hexanol molar fractions. In addition, water produces an increase in the proton exchange rate between donor/acceptor molecules at all n-hexanol molar fractions.