Highly soluble bisurea derivatives for anion recognition.

Highly soluble bisurea derivatives having 1,2-phenoxyethane (receptors 2) and 1,2-ethoxyethane (3) moieties as spacer groups were designed and prepared based on previously reported receptors with the 2,2'-binaphthyl group as a spacer (1). The receptors can be prepared in fewer steps from commercially available starting materials. The solubilities and anion recognition abilities were evaluated by UV-vis and NMR spectral methods. Receptors 2 and 3 bearing a flexible linker showed good solubilities in common organic solvents such as CHCl3, MeCN, 2-butanone, toluene, and THF. Although the anion recognition abilities of receptors 2 and 3 were lower than those of receptors 1, the greatly improved solubilities of receptors 2 and 3 allow the association of anions under more concentrated conditions for the solubilisation of salts such as lithium chloride in organic solvents.

Anion recognition by silanetriol in acetonitrile.

The anion recognition ability of 2,4,6-triisopropylphenylsilanetriol 5 has been evaluated by 1H NMR titrations in MeCN-d3. The anion recognition ability of silanetriol 5 was greater than those of the structurally related silanediols and silanemono-ol, although less effective than those of 1,3-disiloxane-1,3-diol and 1,3-disiloxane-1,1,3,3-tetraol. From the comparison of the association constants and DFT calculations, all three silanol groups of 5 cooperatively hydrogen bonded to anionic species. The catalytic ability of silanetriol 5 for the addition of indole to ß-nitrostyrene in CH2Cl2 has also been evaluated. Silanetriol 5 acts as a more effective organocatalyst than the corresponding silanediol in this reaction.

Impact of preoperative 6-minute walk distance on long-term prognosis after esophagectomy in patients with esophageal cancer.

BACKGROUND: The 6-minute walk distance (6MWD) is a simple way of assessing exercise capacity. The purpose of this study was to investigate the relationship between preoperative 6MWD and long-term prognosis after esophagectomy. METHODS: This retrospective cohort study involved 108 patients who underwent radical esophagectomy for esophageal cancer between 2013 and 2020. The patients were classified into the short group (SG: 6MWD < 480 m) or the long group (LG: 6MWD ≥ 480 m). To adjust for the background characteristics of both groups, propensity score matching (PSM) analysis was performed and 32 patients were matched from each group. Five-year overall survival (OS) and relapse-free survival (RFS) were analyzed by the Kaplan-Meier method. The log-rank test was used to evaluate differences in survival between the groups. After adjusting for other prognostic factors, the Cox proportional hazards model was used to investigate the impact of preoperative 6MWD on long-term prognosis. RESULTS: The median follow-up period was 923 days. Thirty-three deaths were recorded during the study period. After PSM, 5-year OS following surgery was 29.2 and 66.1% (p = 0.003) and 5-year RFS was 27.9 and 58.6% (p = 0.021) in the SG and LG, respectively. In Cox proportional hazards analysis, the SG was a significant independent risk factor for OS (hazard ratio 3.33; 95% confidence interval 1.37-8.11, p = 0.008) and RFS (hazard ratio 2.30; 95% confidence interval 1.08-4.88, p = 0.030). CONCLUSION: The preoperative 6MWD is useful for evaluating exercise capacity and predicting the long-term outcome in patients undergoing esophagectomy.

Skin-related enzyme inhibitory activity by hydrolyzable polyphenols in water chestnut (Trapa natans) husk.

Water chestnut is a floating leaf plant native to Asia and Europe. Its fruit has long been used as an edible and herbal medicine. Water chestnut contains many polyphenols and its consumption can prevent lifestyle-related diseases because it has a suppressive effect on postprandial blood glucose elevation; however, its suitability as a cosmetic material is unknown. Therefore, this study aimed at investigating the antiaging effect of polyphenols contained in the husk of the devil water chestnut (Trapa natans). Six hydrolyzable polyphenols-1,6-di-O-galloyl-ß-d-glucopyranose, 1,2,6-tri-O-galloyl-ß-d-glucopyranose, 1,6-di-O-galloyl-2,3-O-(S)-hexahydroxydiphenoyl-ß-d-glucopyranose (nobotanin D), eugeniin, 1,2,3,6-tetra-O-galloyl-ß-d-glucopyranose, and trapain-were collected and isolated from the water chestnut husk. These polyphenols showed high antioxidant and antiglycation activities. In addition, inhibitory activities against hyaluronidase, elastase, and collagenase were observed. Especially, eugeniin and trapain, which have many gallic acids and a hexahydroxy-biphenyl group, showed high inhibitory activities. Thus, the polyphenols in water chestnut are beneficial for antiaging effects.

Characterization of a novel polymeric prodrug of an antibacterial agent synthesized by mechanochemical solid-state polymerization.

Polycrystalline methacryloyl monomers of the antibacterial drug nalidixic acid with an anhydride bond to the drug carboxyl group were prepared. The physicochemical properties of the synthesized vinyl monomer were characterized using X-ray powder diffraction, thermal analysis, and polarized light microscopy measurements. Mechanochemical solid-state polymerization of the resulting monomers was carried out to yield a novel polymeric prodrug. The in vitro hydrolysis behavior of the polymeric prodrug indicated that the release rate of drug from the polymeric prodrug was clearly dependent on the pH value of the hydrolysis solution. Moreover, sustained release of the drug at an almost constant rate for more than 10 hr was shown in both neutral and alkaline solutions. The results suggest that anhydride-based polymeric prodrugs could be potentially useful in colon targeted drug delivery systems.

Induced Circular Dichroism of Achiral Cyclic Bisurea via Hydrogen Bonds with Chiral Carboxylates.

Chiral induction properties of achiral bisurea derivatives by binding tetrabutylammonium salts of N-acetylated chiral carboxylates (Ac-AlaO-, Ac-ValO-, Ac-LeuO-, and Ac-PheO-) was studied. Ultraviolet-visible titrations showed 1:1 complex formation between the bisureas and the carboxylates. The calculated association constants of cyclic bisurea (1a) were 5-10 times larger than those of the acyclic derivative (2), and 1a showed the highest binding affinity for Ac-LeuO-. While circular dichroism (CD) of both 1a and 2 was induced upon the addition of chiral carboxylates, the CD intensity of 1a was greater than that of 2. Especially, the intensity induced by chiral Ac-LeuO- was the greatest. 1H nuclear magnetic resonance titrations and density functional theory (DFT) calculations showed the cooperative hydrogen bonds of four urea N-Hs and the carboxylate group and the CH-π interactions between a naphthyl unit of 1a and the methyl moieties of Ac-LeuO-. Furthermore, DFT calculations suggested that the twisted anticlockwise conformation of 1a would be dominantly induced by Ac-d-LeuO-. The CD intensity changes of 1a showed a good linear relationship with the enantiomeric excess (ee) values of Ac-LeuO-; therefore, 1a could be utilized as a stereodynamic chiral probe for determining the ee of chiral anions.

Kinetic analysis of mechanoradical formation during the mechanolysis of dextran and glycogen.

A detailed electron spin resonance (ESR) analysis of mechanically induced free radicals (mechanoradicals) formation of glucose-based polysaccharides, dextran (Dx) and glycogen (Gly) was performed in comparison with amylose mechanoradicals. The ESR spectra of the samples mechanically fractured at room temperature were multicomponent. The radical concentration of Dx and Gly mechanoradicals gradually decreased during vibratory milling after reaching the maximum value. Although the molecular weight of Dx or the particle diameter of Gly steeply diminished until reaching the each maximum value of radical concentration, after that the molecular weight or the particle diameter slowly decreased. These results suggested that Dx and Gly mechanoradicals might be more unstable than amylose radicals possessing an intramolecular helical structure due to the branched structure.

Chloride Selective Macrocyclic Bisurea Derivatives with 2,2'-Binaphthalene Moieties as Spacers.

A cyclic bisurea derivative 2a has been successfully prepared from the corresponding diamine and diisocyanate in the presence of tetrabutylammonium chloride as a template. A more soluble cyclic bisurea 2b has also been prepared by introduction of sterically bulky tert-butyl groups. X-ray crystal analyses of [2a·Cl]- and [2b·Cl]- revealed that overall structure was saddle like and the chloride anion was located in the center of the cavity. The bound chloride anion was hydrogen bonded by four N-H of urea groups and weakly hydrogen bonded by four 1-C-H of naphthyl groups, respectively. After removal of the bound chloride anions of [2b·Cl]- with silver nitrate, two different X-ray crystals of free 2b were obtained; one was intermolecular hydrogen bonded shrunken structure and the other was extended structure. Receptor 2b showed large binding ability for Cl-, however, the selectivity for Cl- against basic anions, such as AcO- and F-, has been insufficient. In aqueous MeCN, the association constant of 2b for Cl- was reduced but still large, and the selectivity for hydrophobic Cl- was greatly improved. In this solvent, 2b also selectively recognized alkaline metal chloride salts. Therefore, cyclic bisurea 2b is highly selective and effective Cl- selective receptor.

Development of Novel Polymeric Prodrugs Synthesized by Mechanochemical Solid-State Copolymerization of Hydroxyethylcellulose and Vinyl Monomers.

Novel polymeric prodrugs were synthesized by mechanochemical solid-state copolymerization of hydroxyethylcellulose and the methacryloyloxy derivative of 5-fluorouracil (5-FU). Copolymerization was about 94% complete after 4 h, and the polymeric prodrug was quantitatively obtained after 14 h of reaction. The number average molecular weight (Mn) and polydispersity (H) of the polymeric prodrug were 39000 g/mol and 6.20, respectively. Mechanical fracturing of the polymer in a stainless steel twin-shell blender improved these properties (Mn=16000 g/mol and H=1.94). 5-FU was sustainably released from the polymeric prodrugs, and the rate was not affected by the molecular weight or molecular weight distribution of the prodrug under the experimental conditions used. These results suggest that novel polymeric prodrugs composed of a polysaccharide and a synthetic polymer can be fabricated by mechanochemical solid-state copolymerization under anaerobic conditions.

Novel pH-responsive polymeric micelles prepared through self-assembly of amphiphilic block copolymer with poly-4-vinylpyridine block synthesized by mechanochemical solid-state polymerization.

We fabricated polymeric micelles containing 5-fluorouracil (5-FU) or fluorescein using the amphiphilic block copolymer, poly-4-vinylpyridine-b-6-O-methacryloyl galactopyranose. Although the polymeric micelles were stable at pH 7.4, they readily decomposed at pH 5, resulting in near complete release of 5-FU. Uptake of polymeric micelles containing fluorescein by HepG2 and HCT116 cells was also investigated. With both cell types, strong fluorescence was observed after a 12-h incubation, but the fluorescence weakened after 24 h of incubation. The fluorescein incorporated into the polymeric micelles was released into acidic organelles (endosome and/or lysosome), from which it diffused throughout the cell. The cytotoxicity of polymeric micelles containing 5-FU was evaluated against HepG2 cells using a CCK-8 assay. The results suggest that polymeric micelles containing 5-FU are more cytotoxic to HepG2 cells than free 5-FU.

Synthesis of unnatural alkaloid scaffolds by exploiting plant polyketide synthase.

HsPKS1 from Huperzia serrata is a type III polyketide synthase (PKS) with remarkable substrate tolerance and catalytic potential. Here we present the synthesis of unnatural unique polyketide-alkaloid hybrid molecules by exploiting the enzyme reaction using precursor-directed and structure-based approaches. HsPKS1 produced novel pyridoisoindole (or benzopyridoisoindole) with the 6.5.6-fused (or 6.6.5.6-fused) ring system by the condensation of 2-carbamoylbenzoyl-CoA (or 3-carbamoyl-2-naphthoyl-CoA), a synthetic nitrogen-containing nonphysiological starter substrate, with two molecules of malonyl-CoA. The structure-based S348G mutant not only extended the product chain length but also altered the cyclization mechanism to produce a biologically active, ring-expanded 6.7.6-fused dibenzoazepine, by the condensation of 2-carbamoylbenzoyl-CoA with three malonyl-CoAs. Thus, the basic nitrogen atom and the structure-based mutagenesis enabled additional C─C and C─N bond formation to generate the novel polyketide-alkaloid scaffold.

Dextran-based nanoparticles with 5-FU-conjugated polymethacrylate segments for drug delivery: Synthesis of amphiphilic graft copolymers by mechanochemical solid-state polymerization and characterization.

Dextran (Dx) is a biodegradable and biocompatible polysaccharide, thus promising as a drug delivery carrier for tumor therapy. Herein, we applied mechanical energy to a high molecular weight Dx to control its molecular weight and simultaneously generate mechanoradicals. The solid-state polymerization of methacrylate- or methacrylamide derivatives initiated with Dx mechanoradicals showed polymer conversion of >95 %, yielding Dx-based graft copolymers with molecular weights of approximately 30,000 g mol-1. The Dx-based graft copolymers with hydrophobic segments formed nanoparticles with a particle size of 25-35 nm in an aqueous solution. The anti-pancreatic tumor drug 5-fluorouracil (5-FU) was covalently conjugated onto the hydrophobic segments of the amphiphilic Dx, and the nanoparticles were also prepared. The drug release profile from 5-FU-conjugated nanoparticles corresponded well to the Korsmeyer-Peppas model applied to drug release from matrix substrates, and was also immensely predicted by the Logistic and Gompertz curves. The 5-FU-conjugated nanoparticles showed cytotoxicity against the pancreatic adenocarcinoma cell lines (BxPC-3) that were not significantly inferior to the 5-FU positive group. Furthermore, the fluorescein-labeled nanoparticles internalized into BxPC-3 within 6 h and actively migrated into the cytosol. These results suggest that Dx-based graft copolymers with hydrophobic segments might be used to enhance therapeutic activity.

Skeletal muscle mass during chemotherapy for haematological malignancies: a retrospective study.

OBJECTIVE: This study investigated whether baseline or alteration in muscle mass affects complications during chemotherapy or overall survival (OS) in haematological malignancies. METHODS: Skeletal Muscle Index (SMI) was evaluated by bioimpedance analysis before and after chemotherapy in patients with haematological malignancies, and the association between muscle mass and clinical data was retrospectively analysed. RESULTS: Exactly 104 patients were enrolled, with a mean age of 62.2 years. SMI was 7.85 and 6.08 in male and female patients under 65 years and 7.10 and 5.92 over 65 years, before chemotherapy, respectively. Lower baseline SMI was not correlated with worse OS in total patients (p=0.915). After a median measurement interval of 30 days after chemotherapy (n=67), body weight and SMI decreased by 2.73% and 2.87% (mean), respectively. The decrease in body weight correlated with the loss of trunk muscle mass (R2=0.2107) but was more strongly associated with the loss of lower limbs muscle mass (R2=0.3985). The muscle mass of lower limbs significantly decreased in lymphoma patients who experienced febrile neutropenia (-0.42% vs -6.04%, p=0.040). OS significantly decreased in lymphoma patients with loss of lower limbs muscle ≥2.8% (p=0.0327). CONCLUSIONS: Muscle loss occurred following anticancer treatments, significantly contributing to worse outcomes. Body composition assessment and relevant multimodal prevention of muscle loss may be vital for patients receiving chemotherapy for haematological malignancies.

Fluorescence Sensing of Anions by Silanediols Bearing Substituted Naphthyl Groups.

Silanediols bearing naphthyl moieties substituted at 5-position with an electron-withdrawing cyano group and an electron-donating N,N-dimethylamino group, respectively, have been prepared and characterized. The substituents on the naphthyl moieties strongly influence the reactivity, photophysical properties, and sensing abilities for anions. The silanediol bearing 1-(5-N,N-dimethylaminonaphthyl) groups exhibited large Stokes shifts based on intramolecular charge transfer and large quantum yields in organic solvents. The silanediol showed favorable ratiometric fluorescence responses of upon the addition of biologically important anions, AcO- and H2 PO4 - with the association constants of 4.08×104 and 8.76×103  mol-1 dm3 , respectively.

Impact of postoperative physical activity on the development of pneumonia in the subacute phase after esophagectomy in patients with esophageal cancer: A retrospective cohort study.

PURPOSE: Physical activity is important to improve recovery following surgery. This study investigated the impact of physical activity on the development of pneumonia after radical esophagectomy in patients with thoracic esophageal cancer in the subacute phase from postoperative day 11 to hospital discharge. METHODS: This retrospective cohort study included 83 patients who underwent radical esophagectomy for esophageal cancer between 2016 and 2022. Physical activity was measured using an activity tracker, and the average number of steps between postoperative days 8 and 10 was examined. The primary outcome was pneumonia (Clavien-Dindo classification 2 or higher) developing between postoperative day 11 and hospital discharge. We used the receiver operating characteristic (ROC) curve analysis to calculate the optimal cutoff value of physical activity that can predict the development of pneumonia and define low physical activity. We used logistic regression analysis to investigate the impact of low physical activity on postoperative pneumonia. RESULTS: Pneumonia developed in 10 patients (12.0%) during the observation period. The optimal cutoff value of physical activity for predicting pneumonia was 1494 steps per day (sensitivity: 60.0%, specificity: 89.0%, area under the curve: 0.743). In multivariate analysis, low physical activity was an independent predictor of incident pneumonia [odds ratio: 12.10, 95% confidence interval: 2.21-65.90, p = 0.004], with adjustment for age, gastric tube reconstruction route, and postoperative recurrent nerve palsy. CONCLUSIONS: Physical activity following radical esophagectomy in patients with thoracic esophageal cancer was an independent predictor of the development of pneumonia in the subacute phase after radical esophagectomy.

Synthesis and Characterization of Cyclotri- and Tetrasiloxanes with Pyrenyl Groups.

Cyclosiloxanes directly bearing polyaromatic groups on silicon atoms have scarcely been reported. Herein, hexa(1-pyrenyl)cyclotrisiloxane (2) and octa(1-pyrenyl)cyclotetrasiloxane (3) were successfully prepared from di(1-pyrenyl)silanediol (1) in the presence of a weak base such as tetraethylammonium acetate and triethylamine in MeCN. The structure of the cyclosiloxanes bearing multiple pyrenyl groups in the solid and solution states was evaluated by NMR, X-ray crystallography, and density functional theory (DFT) calculations. All pyrenyl groups of 2 were oriented outward, and no π-π stacking of adjacent pyrenyl groups was observed. However, all pairs of adjacent pyrenyl groups at 1- and 3-positions in 3 are oriented in the same direction and were π-π stacked with respect to each other. The UV-vis spectra of 2 and 3 in organic solvents showed a slight broadening of the peaks, as observed for typical pyrene derivatives. Interestingly, the fluorescence spectra of 2 showed small monomer and strong excimer emissions; however, those of 3 showed only a strong excimer emission in all solvents. Partially pyrenylated cyclotri- and tetrasiloxanes (compounds 4 and 5) showed solvent-dependent monomer and excimer spectra as observed for di(1-pyrenyl)silane derivatives, implying that the excimer emissions of 2 and 3 arise from mainly geminal and vicinal pyrenyl groups, respectively.

Characteristics of the stand-to-sit motion in healthy older women†:†Evaluation of sitting impact by measurement of ground reaction forces.

Objectives : The aims of this study were to examine the biomechanics of StandTS movements in older adults and to identify their optimal StandTS motion by measuring sitting impact forces. Methods : Healthy older women (n = 17) and healthy young women (n = 18) were asked to perform SitTS and StandTS motions at a natural speed using a chair. We measured the ground reaction forces from the participants' feet and the chair, the angle of the trunk and ankle, vertical velocity, and postural muscle activities using a force plate, motion analyzer, and electromyography, respectively. Results : Sitting impact force was significantly greater in the older women than in the young women during the StandTS motion. There was a significant difference between the trunk angle and the ankle angle during the StandTS motion and sitting impact force had a significant negative correlation with the ankle joint motion in the older women. Conclusions : The ankle joint strategy was characterized by body sway resembling a single-segment-inverted pendulum and suggests that this response is less developed in the older adult. These results indicate that the ankle joint strategy may be an important factor involved in the sitting impact force. J. Med. Invest. 69 : 278-286, August, 2022.

Impact of sarcopenia defined by carina-level skeletal muscle mass on the long-term prognosis of patients with idiopathic pulmonary fibrosis.

BACKGROUND: Sarcopenia, defined using abdominal computed tomography (CT), has been used as a prognostic marker for patients with idiopathic pulmonary fibrosis (IPF). However, no consensus on the impact of sarcopenia as defined using chest CT exists. Therefore, this study aimed to investigate the impact of sarcopenia, defined using CT at the carina-level, on the long-term prognosis of patients with IPF. METHODS: This single-center retrospective cohort study included 117 patients with IPF. Sarcopenia was defined as skeletal muscle mass measured at the carina-level on chest CT images. All-cause mortality was analyzed using the Kaplan-Meier method, and the log-rank test was used to evaluate the differences between sarcopenia and non-sarcopenia groups. A Cox proportional hazards regression model was used to analyze the impact of sarcopenia on all-cause mortality in model 1 with adjustment for body mass index and gender-age-physiology stage as a confounding factor and in model 2 with sex, age, and% forced vital capacity (FVC). RESULTS: The median follow-up period was 956 days, and 57 deaths were recorded. The sarcopenia group had a significantly lower survival rate than the non-sarcopenia group. The multivariate Cox proportional hazards analysis revealed that sarcopenia was a significant predictor of all-cause mortality in models 1 and 2. In patients with no diffusing capacity for carbon monoxide (DLCO) measurement, sarcopenia was a significant prognostic predictor of all-cause mortality independent of%FVC. CONCLUSION: Sarcopenia, defined at the carina level, is a risk factor for all-cause mortality in patients with IPF. Assessment of sarcopenia by CT imaging is useful and less burdensome in patients with IPF.

Allogeneic haematopoietic stem cell transplantation and patient falls: impact of lower extremity muscle strength.

OBJECTIVES: Patients undergoing allogeneic haematopoietic stem cell transplantation (allo-HSCT) have a higher risk of falls than those receiving other therapies for haematological disorders. This study aimed to investigate the impact of pretransplant lower extremity muscle strength (LEMS) on post-transplant falls. METHODS: In this retrospective cohort study, patients aged ≥18 years who underwent allo-HSCT were included. All data were extracted from medical records. LEMS was defined as the knee extension force measured by a handheld dynamometer divided by the patient's weight. The receiver operating characteristic (ROC) curve was used to calculate the optimal LEMS cut-off value for prediction of falls. Patients were categorised into low and normal LEMS groups based on the cut-off value. The impact of pretransplant LEMS on post-transplant falls was analysed using a Cox proportional hazards model. RESULTS: In total, 101 patients were analysed. During the observation period, falls occurred in 32 patients (31.7%). The ROC curve analysis results showed that the optimal LEMS cut-off value for prediction of falls was 45.4% per body weight. In multivariate analysis, pretransplant low LEMS was a significant predictor of falls in model 1 with patient characteristics as a confounding factor and model 2 with medications-inducing falls as a confounding factor, respectively (model 1: HR 3.23, 95% CI 1.37 to 7.64; model 2: HR 2.82, 95% CI 1.20 to 6.59). CONCLUSIONS: Pretransplant LEMS was a significant predictor of post-transplant falls. The results of this study may help to prevent falls in patients undergoing allo-HSCT.

Characterization of novel pH-sensitive polymeric micelles prepared by the self-assembly of amphiphilic block copolymer with poly-4-vinylpyridine block synthesized by mechanochemical solid-state polymerization.

We fabricated novel pH-sensitive polymeric micelles consisting of amphiphilic block copolymer containing pyridyl groups as side chains in the hydrophobic block. The number average particle diameter of the polymeric micelles at pH 7 was approximately 200 nm. A decrease in pH resulted in deformation of the polymeric micelles over a very narrow pH range (between pH 5.7 and 5.6). Interestingly, micellization and demicellization occurred reversibly in this narrow pH range. Polymeric micelles incorporating 5-fluorouracil (5FU) were also prepared. Decreasing the pH of this polymeric micelle solution from 7 to 5.5 resulted in the rapid release of 5FU at pH 5.6; the drug was completely released within 30 min. These results suggest that deformation of the polymeric micelles caused the rapid release of 5FU.