Unlocking the Use of LiCl as an Inexpensive Salt for Lithium-Ion Batteries with a Novel Anion Receptor.

Lithium chloride (LiCl) is an inexpensive and environmentally friendly salt abundant in the ocean. However, the insolubility of LiCl in conventional electrolyte solvents prevents the practical use of LiCl for lithium-ion batteries. Here, we report a novel method to increase the solubility of LiCl in a conventional electrolyte. The solubility of LiCl in ethylene carbonate (EC)/dimethyl carbonate (DMC) (1/1, v/v) is about quadrupled by adding a small amount of anion receptor with two urea moieties as recognition sites connecting with an ether chain. Anion receptor is an organic molecule that can associate with anions. Our anion receptor is able to associate with chloride anion. The ionic conductivity of LiCl in EC/DMC increased from 0.023 mS cm-1 (without an anion receptor) to 0.075 mS cm-1 (with a 0.05 M anion receptor). The electrolyte in the presence of a 0.05 M receptor exhibits higher ionic conductivity, rate capability, and cyclability than the electrolyte without the receptor.

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.

Characterization of soticlestat, a novel cholesterol 24-hydroxylase inhibitor, in acute and chronic neurodegeneration models.

We investigated whether soticlestat (TAK-935), a newly discovered cholesterol 24-hydroxylase (CH24H) inhibitor now in phase 3 clinical trials for Dravet and Lennox-Gastaut syndromes, has effects on neurodegeneration in both chronic and acute animal models associated with glutamate hyperexcitation. Soticlestat was administered at doses that approximately halve 24S-hydroxycholesterol in both experiments. In the kainic acid (KA)-induced acute hippocampal degeneration model, soticlestat ameliorated inflammatory cytokine expression, hippocampal degeneration, and memory impairment. We ruled out the possibility that soticlestat directly interferes with KA binding to the KA receptor, or that 24S-hydroxycholesterol modulates KA receptor signaling, by conducting receptor binding and cell death assays. In the PS19 chronic degeneration model of tauopathy, treatment effects were observed in neurodegeneration markers. Notably, there was a significant correlation between the levels of brain 24S-hydroxycholesterol and a proinflammatory cytokine, tumor necrosis factor-α, which is implicated in cognitive decline and lowering of seizure threshold. This is the first study demonstrating that CH24H inhibition can alleviate neurodegeneration concomitant with neuroinflammation. Herein, we discuss the interplay among 24S-hydroxycholesterol production, neuroinflammation, and excitotoxicity. Effects on neurodegeneration and neuroinflammation demonstrated in two preclinical models suggest that soticlestat is effective in ameliorating seizures and addressing cognitive dysfunction in seizure disorders.

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.

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.

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.

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.

Cholesterol 24-hydroxylase is a novel pharmacological target for anti-ictogenic and disease modification effects in epilepsy.

Therapies for epilepsy mainly provide symptomatic control of seizures since most of the available drugs do not target disease mechanisms. Moreover, about one-third of patients fail to achieve seizure control. To address the clinical need for disease-modifying therapies, research should focus on targets which permit interventions finely balanced between optimal efficacy and safety. One potential candidate is the brain-specific enzyme cholesterol 24-hydroxylase. This enzyme converts cholesterol to 24S-hydroxycholesterol, a metabolite which among its biological roles modulates neuronal functions relevant for hyperexcitability underlying seizures. To study the role of cholesterol 24-hydroxylase in epileptogenesis, we administered soticlestat (TAK-935/OV935), a potent and selective brain-penetrant inhibitor of the enzyme, during the early disease phase in a mouse model of acquired epilepsy using a clinically relevant dose. During soticlestat treatment, the onset of epilepsy was delayed and the number of ensuing seizures was decreased by about 3-fold compared to vehicle-treated mice, as assessed by EEG monitoring. Notably, the therapeutic effect was maintained 6.5 weeks after drug wash-out when seizure number was reduced by about 4-fold and their duration by 2-fold. Soticlestat-treated mice showed neuroprotection of hippocampal CA1 neurons and hilar mossy cells as assessed by post-mortem brain histology. High throughput RNA-sequencing of hippocampal neurons and glia in mice treated with soticlestat during epileptogenesis showed that inhibition of cholesterol 24-hydroxylase did not directly affect the epileptogenic transcriptional network, but rather modulated a non-overlapping set of genes that might oppose the pathogenic mechanisms of the disease. In human temporal lobe epileptic foci, we determined that cholesterol 24-hydroxylase expression trends higher in neurons, similarly to epileptic mice, while the enzyme is ectopically induced in astrocytes compared to control specimens. Soticlestat reduced significantly the number of spontaneous seizures in chronic epileptic mice when was administered during established epilepsy. Data show that cholesterol 24-hydroxylase contributes to spontaneous seizures and is involved in disease progression, thus it represents a novel target for chronic seizures inhibition and disease-modification therapy in epilepsy.

Anticonvulsive properties of soticlestat, a novel cholesterol 24-hydroxylase inhibitor.

OBJECTIVE: The formation of 24S-hydroxycholesterol is a brain-specific mechanism of cholesterol catabolism catalyzed by cholesterol 24-hydroxylase (CYP46A1, also known as CH24H). CH24H has been implicated in various biological mechanisms, whereas pharmacological lowering of 24S-hydroxycholesterol has not been fully studied. Soticlestat is a novel small-molecule inhibitor of CH24H. Its therapeutic potential was previously identified in a mouse model with an epileptic phenotype. In the present study, the anticonvulsive property of soticlestat was characterized in rodent models of epilepsy that have long been used to identify antiseizure medications. METHODS: The anticonvulsive property of soticlestat was investigated in maximal electroshock seizures (MES), pentylenetetrazol (PTZ) acute seizures, 6-Hz psychomotor seizures, audiogenic seizures, amygdala kindling, PTZ kindling, and corneal kindling models. Soticlestat was characterized in a PTZ kindling model under steady-state pharmacokinetics to relate its anticonvulsive effects to pharmacodynamics. RESULTS: Among models of acutely evoked seizures, whereas anticonvulsive effects of soticlestat were identified in Frings mice, a genetic model of audiogenic seizures, it was found ineffective in MES, acute PTZ seizures, and 6-Hz seizures. The protective effects of soticlestat against audiogenic seizures increased with repetitive dosing. Soticlestat was also tested in models of progressive seizure severity. Soticlestat treatment delayed kindling acquisition, whereas fully kindled animals were not protected. Importantly, soticlestat suppressed the progression of seizure severity in correlation with 24S-hydroxycholesterol lowering in the brain, suggesting that 24S-hydroxycholesterol can be aggressively reduced to produce more potent effects on seizure development in kindling acquisition. SIGNIFICANCE: The data collectively suggest that soticlestat can ameliorate seizure symptoms through a mechanism distinct from conventional antiseizure medications. With its novel mechanism of action, soticlestat could constitute a novel class of antiseizure medications for treatment of intractable epilepsy disorders such as developmental and epileptic encephalopathy.

Soticlestat, a novel cholesterol 24-hydroxylase inhibitor, reduces seizures and premature death in Dravet syndrome mice.

OBJECTIVE: Dravet syndrome is a severe developmental and epileptic encephalopathy (DEE) most often caused by de novo pathogenic variants in SCN1A. Individuals with Dravet syndrome rarely achieve seizure control and have significantly elevated risk for sudden unexplained death in epilepsy (SUDEP). Heterozygous deletion of Scn1a in mice (Scn1a+/- ) recapitulates several core phenotypes, including temperature-dependent and spontaneous seizures, SUDEP, and behavioral abnormalities. Furthermore, Scn1a+/- mice exhibit a similar clinical response to standard anticonvulsants. Cholesterol 24-hydroxlase (CH24H) is a brain-specific enzyme responsible for cholesterol catabolism. Recent research has indicated the therapeutic potential of CH24H inhibition for diseases associated with neural excitation, including seizures. METHODS: In this study, the novel compound soticlestat, a CH24H inhibitor, was administered to Scn1a+/- mice to investigate its ability to improve Dravet-like phenotypes in this preclinical model. RESULTS: Soticlestat treatment reduced seizure burden, protected against hyperthermia-induced seizures, and completely prevented SUDEP in Scn1a+/- mice. Video-electroencephalography (EEG) analysis confirmed the ability of soticlestat to reduce occurrence of electroclinical seizures. SIGNIFICANCE: This study demonstrates that soticlestat-mediated inhibition of CH24H provides therapeutic benefit for the treatment of Dravet syndrome in mice and has the potential for treatment of DEEs.

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.

Soticlestat, a novel cholesterol 24-hydroxylase inhibitor shows a therapeutic potential for neural hyperexcitation in mice.

Cholesterol 24-hydroxylase (CH24H) is a brain-specific enzyme that converts cholesterol into 24S-hydroxycholesterol, the primary mechanism of cholesterol catabolism in the brain. The therapeutic potential of CH24H activation has been extensively investigated, whereas the effects of CH24H inhibition remain poorly characterized. In this study, the therapeutic potential of CH24H inhibition was investigated using a newly identified small molecule, soticlestat (TAK-935/OV935). The biodistribution and target engagement of soticlestat was assessed in mice. CH24H-knockout mice showed a substantially lower level of soticlestat distribution in the brain than wild-type controls. Furthermore, brain-slice autoradiography studies demonstrated the absence of [3H]soticlestat staining in CH24H-knockout mice compared with wild-type mice, indicating a specificity of soticlestat binding to CH24H. The pharmacodynamic effects of soticlestat were characterized in a transgenic mouse model carrying mutated human amyloid precursor protein and presenilin 1 (APP/PS1-Tg). These mice, with excitatory/inhibitory imbalance and short life-span, yielded a remarkable survival benefit when bred with CH24H-knockout animals. Soticlestat lowered brain 24S-hydroxycholesterol in a dose-dependent manner and substantially reduced premature deaths of APP/PS1-Tg mice at a dose lowering brain 24S-hydroxycholesterol by approximately 50%. Furthermore, microdialysis experiments showed that soticlestat can suppress potassium-evoked extracellular glutamate elevations in the hippocampus. Taken together, these data suggest that soticlestat-mediated inhibition of CH24H may have therapeutic potential for diseases associated with neural hyperexcitation.

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.

Anti-sortilin1 Antibody Up-Regulates Progranulin via Sortilin1 Down-Regulation.

Progranulin (PGRN) haploinsufficiency associated with loss-of-function mutations in the granulin gene causes frontotemporal dementia (FTD). This suggests that increasing PGRN levels could have promising therapeutic implications for patients carrying GRN mutations. In this study, we explored the therapeutic potential of sortilin1 (SORT1), a clearance receptor of PGRN, by generating and characterizing monoclonal antibodies against SORT1. Anti-SORT1 monoclonal antibodies were generated by immunizing Sort1 knockout mice with SORT1 protein. The antibodies were classified into 7 epitope bins based on their competitive binding to the SORT1 protein and further defined by epitope bin-dependent characteristics, including SORT1-PGRN blocking, SORT1 down-regulation, and binding to human and mouse SORT1. We identified a positive correlation between PGRN up-regulation and SORT1 down-regulation. Furthermore, we also characterized K1-67 antibody via SORT1 down-regulation and binding to mouse SORT1 in vivo and confirmed that K1-67 significantly up-regulated PGRN levels in plasma and brain interstitial fluid of mice. These data indicate that SORT1 down-regulation is a key mechanism in increasing PGRN levels via anti-SORT1 antibodies and suggest that SORT1 is a potential target to correct PGRN reduction, such as that in patients with FTD caused by GRN mutation.

Silanediol Anion Binding and Enantioselective Catalysis.

Silanediols possess unique and complementary catalytic activity in reactions that are likely to proceed through anion binding. This article directly compares silanediols, thioureas, and squaramides in three separate anion-binding processes. The catalytic abilities of select members of each family are directly correlated to association constant.

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.

Kanamycin and its derivative, arbekacin: significance and impact.

On the occasion of the 60th anniversary of the discovery (1957) of kanamycin (KM), a series of research achievements on KM and its semisynthetic derivative Arbekacin (ABK) are outlined. KM was first used clinically in 1958 and was appreciated for its remarkable curing effect on various bacterial infections, especially tuberculosis. ABK is a KM derivative rationally semisynthesized to overcome KM resistance due to enzymatic phosphorylation and acetylation. Since its approval in 1990 as an anti-MRSA drug, ABK has been and still is effectively used in chemotherapy because MRSA rarely develops high ABK-resistance. Research that illuminated the unique features of ABK enabling it to resist the development of resistance by MRSA are also described.

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.

Silanediol-Catalyzed Chromenone Functionalization.

Promising levels of enantiocontrol are observed in the silanediol-catalyzed addition of silyl ketene acetals to benzopyrylium triflates. This rare example of enantioselective, intermolecular chromenone functionalization with carbonyl-containing nucleophiles has potential applications in the synthesis of bioactive chromanones and tetrahydroxanthones.