Anticancer approach by targeted activation of a global inhibitor of sialyltransferases with acrolein.

Cells are covered with a thick layer of sugar molecules known as glycans. Abnormal glycosylation is a hallmark of cancer, and hypersialylation increases tumor metastasis by promoting immune evasion and inducing tumor cell invasion and migration. Inhibiting sialylation is thus a potential anticancer treatment strategy. However, targeting sialic acids is difficult because of the lack of selective delivery tools. Here, we present a prodrug strategy for selectively releasing the global inhibitor of sialylation peracetylated 3Fax-Neu5Ac (PFN) in cancer cells using the reaction between phenyl azide and endogenous acrolein, which is overproduced in most cancer cells. The prodrug significantly suppressed tumor growth in mice as effectively as PFN without causing kidney dysfunction, which is associated with PFN. The use of sialylated glycans as immune checkpoints is gaining increasing attention, and the proposed method for precisely targeting aberrant sialylation provides a novel avenue for expanding current cancer treatments.

Study on the Extrapolability of Current Tumorgenicity Test With Mice by Comparing the Syngeneic or Allogeneic Mouse Transplantation Model.

The extrapolability of the current tumorigenicity test performed by transplanting human cell product into immunodeficient (NOG) mice was investigated. For this purpose, the susceptibility to form teratomas of NOG mice was assessed by transplanting undifferentiated human-induced pluripotent stem cells (hiPSCs) as positive control cells via the liver, striatum, or tail vein and evaluating the TPD50 value (dose required to form teratomas in half of the transplanted mice). This was then compared to the TPD50 of syngeneic or allogeneic mouse models. The TPD50 of C57/BL/6(B6)-iPSC or 129/Ola(129)-embryonic stem cell (ESC) transplanted into the liver of syngeneic mice was 4.08 × 105 and 4.64 × 104 cells, respectively, while the TPD50 of hiPSC administered into the liver of NOG mice was 4.64 × 104 cells. The TPD50 of B6-miPSC-synergic, 129-mESC-synergic, or 129-cell/B6 allogeneic transplantation into the striatum was 5.09 × 102, 1.0 × 104, and 3.73 × 104 cells, respectively, while that of hiPSC/NOG mice was 1.0 × 103 cells. The TPD50 for B6-miPSC or 129-mESC syngeneic tail vein infusion was 3.16 × 106 or 5.62 × 106 cells, respectively, while no incidence was observed from 1 × 107 B6-miPSCs in 129 mice or hiPSCs in NOG mice infusion study. Although the number of data sets was limited, these data indicate that the teratoma formation from transplanted undifferentiated hiPSCs via the liver or striatum in NOG mice is comparable to that in syngeneic or allogeneic mouse transplantation model, suggesting that the result of the current tumorigenicity test in NOG mice would provide useful information to infer the incidence of teratoma from residual undifferentiated hPSCs in hPSC-derived products after transplantation.

The validation of a Japanese version of the New Freezing of Gait Questionnaire (NFOG-Q).

OBJECTIVE: This study aimed to develop a Japanese version of the New Freezing of Gait Questionnaire (NFOG-Q) and investigate its validity and reliability. METHODS: After translating the NFOG-Q according to a standardised protocol, 56 patients with Parkinson's disease (PD) were administered it. Additionally, the MDS-UPDRS parts II and III, Hoehn and Yahr (H&Y) stage, and number of falls over 1 month were evaluated. Spearman's correlation coefficients (rho) were used to determine construct validity, and Cronbach's alpha (α) was used to examine reliability. RESULTS: The interquartile range of the NFOG-Q scores was 10.0-25.3 (range 0-29). The NFOG-Q scores were strongly correlated with the MDS-UPDRS part II, items 2.12 (walking and balance), 2.13 (freezing), 3.11 (freezing of gait), and 3.12 (postural stability) and the postural instability and gait difficulty score (rho = 0.515-0.669), but only moderately related to the MDS-UPDRS item 3.10 (gait), number of falls, disease duration, H&Y stage, and time of the Timed Up-and-Go test (rho = 0.319-0.434). No significant correlations were observed between age and the time of the 10-m walk test. The internal consistency was excellent (α = 0.96). CONCLUSIONS: The Japanese version of the NFOG-Q is a valid and reliable tool for assessing the severity of freezing in patients with PD.

Characteristic Evaluation of a 11C-Labeled Leucine Analog, l-α-[5-11C]methylleucine, as a Tracer for Brain Tumor Imaging by Positron Emission Tomography.

Amino acid transporters are upregulated in many cancer cells, and system L amino acid transporters (LAT1-4), in particular, LAT1, which preferentially transports large, neutral, and branched side-chain amino acids, are considered a primary target for cancer positron emission tomography (PET) tracer development. Recently, we developed a 11C-labeled leucine analog, l-α-[5-11C]methylleucine ([5-11C]MeLeu), via a continuous two-step reaction of Pd0-mediated 11C-methylation and microfluidic hydrogenation. In this study, we evaluated the characteristics of [5-11C]MeLeu and also compared the sensitivity to brain tumors and inflammation with l-[11C]methionine ([11C]Met) to determine its potential for brain tumor imaging. Competitive inhibition experiments, protein incorporation, and cytotoxicity experiments of [5-11C]MeLeu were performed in vitro. Further, metabolic analyses of [5-11C]MeLeu were performed using a thin-layer chromatogram. The accumulation of [5-11C]MeLeu in tumor and inflamed regions of the brain was compared with [11C]Met and 11C-labeled (S)-ketoprofen methyl ester by PET imaging, respectively. Transporter assay with various inhibitors revealed that [5-11C]MeLeu is mainly transported via system L amino acid transporters, especially LAT1, into A431 cells. The protein incorporation assay and metabolic assay in vivo demonstrated that [5-11C]MeLeu was neither used for protein synthesis nor metabolized. These results indicate that MeLeu is very stable in vivo. Furthermore, the treatment of A431 cells with various concentrations of MeLeu did not change their viability, even at high concentrations (∼10 mM). In brain tumors, the tumor-to-normal ratio of [5-11C]MeLeu was more elevated than that of [11C]Met. However, the accumulation levels of [5-11C]MeLeu were lower than those of [11C]Met (the standardized uptake value (SUV) of [5-11C]MeLeu and [11C]Met was 0.48 ± 0.08 and 0.63 ± 0.06, respectively). In brain inflammation, no significant accumulation of [5-11C]MeLeu was observed at the inflamed brain area. These data suggested that [5-11C]MeLeu was identified as a stable and safe agent for PET tracers and could help detect brain tumors, which overexpress the LAT1 transporter.

Synthesis and Preclinical Evaluation of 18F-Labeled Ketoprofen Methyl Esters for Cyclooxygenase-1 Imaging in Neuroinflammation.

Cyclooxygenase (COX) is a rate-limiting enzyme in the synthesis of proinflammatory prostanoids from arachidonic acid. In vivo imaging of COX by PET is a potentially powerful tool for assessing the inflammatory response to injury, infection, and disease. We previously reported on a promising PET probe for COX imaging, 11C-labeled ketoprofen methyl ester, which can detect COX-1 activation in models of neuroinflammation and neurodegenerative disorders. In the current study, we aimed to design a fluorine-substituted benzoyl group of ketoprofen (FKTP) and to evaluate its racemate and enantiomers (18F-labeled ketoprofen methyl ester, [18F]FKTP-Me) as PET proradiotracers, potential radiopharmaceuticals for in vivo PET study of COX-1. Methods: We performed nucleophilic aromatic 18F-fluorination to obtain the desired racemic radiolabeled probe, (RS)-[18F]FKTP-Me, at a radiochemical yield of 11%-13%. Subsequent high-performance liquid chromatography separation with a chiral column yielded the desired enantiomerically pure (R)- and (S)-[18F]FKTP-Me. We examined the in vivo properties of (RS)-, (R)-, and (S)-[18F]FKTP-Me in PET studies using rats in which hemispheric inflammation was induced by intrastriatally injecting a lipopolysaccharide. Results: Racemic (RS)-[18F]FKTP-Me and enantiomeric (R)- or (S)-[18F]FKTP-Me were synthesized with radiochemical and chemical purities of more than 99%. The metabolite analysis revealed that the racemic (RS)-[18F]FKTP-Me crossed the blood-brain barrier and entered the brain, where it was subsequently hydrolyzed to its pharmacologically active acid form. PET images revealed a high accumulation of (R)-, (S)-, and (RS)-[18F]FKTP in the inflamed regions in rat brain. Moreover, the accumulated radioactivity of (S)-[18F]FKTP-Me was higher than that of (RS)-[18F]FKTP-Me and (R)-[18F]FKTP-Me, which was correlated with the stereospecific inhibitory activity of FKTP against COX-1. Conclusion: From the results of this study, we conclude that racemic (RS)-[18F]FKTP-Me and its enantiomers could act as proradiotracers of neuroinflammation in rat brain by the association of their hydrolyzed acid forms with COX-1 in inflamed regions. In particular, (S)-[18F]FKTP-Me demonstrated suitable properties as a COX-1-specific probe in PET imaging of neuroinflammation.

Role Played by Receptors for Advanced Glycosylation End Products in Corneal Endothelial Cells after HSV-1 Infection.

Senescence, sterile inflammation, and infection cause dysfunction of corneal endothelial cells, leading to visual morbidity that may require corneal transplantation. With increasing age, the extracellular matrix is modified by non-enzymatic glycation forming advanced glycation end products (AGEs). The modifications are primarily sensed by the receptors for the AGEs (RAGE) and are manifested as a type I interferon response. Interestingly, in our study, human corneal endothelial cells (HCEn) cells did not respond to the typical RAGE ligands, including the AGEs, high mobility group box 1 (HMGB1), and serum amyloid-A (SAA). Instead, HCEn cells responded exclusively to the CpG DNA, which is possessed by typical corneal pathogen, herpes simplex virus-1 (HSV-1). Upon HSV-1 infection, the surface expression of RAGE was increased, and endocytosed HSV-1 was associated with RAGE and CpG DNA receptor, TLR9. RAGE DNA transfection markedly increased interferon-ß secretion by CpG DNA or HSV-1 infection. HSV-1 infection-induced interferon-ß secretion was abolished by TLR9 inhibition and partially by RAGE inhibition. Global transcriptional response analysis confirmed that RAGE and TLR9 were both significantly involved in type I interferon responses. We conclude that RAGE is a sensor of HSV-1 infection and provokes a type I interferon response.

Validation and Reliability of the Japanese Version of the Modified Parkinson Activity Scale (M-PAS).

OBJECTIVE: The Modified Parkinson Activity Scale (M-PAS) is used to identify the most important activity limitations in patients with Parkinson's disease. We developed a Japanese version of the M-PAS and evaluated its reliability and validity. METHODS: Twenty-five patients with Parkinson's disease (median age 71 years old, range 58-83) were enrolled, and two raters used the Japanese version of M-PAS to assess the subjects. The inter-rater reliability was evaluated using Cohen's weighted kappa coefficient for the total score and three domain scores; systematic error was investigated using Bland-Altman analysis. Concurrent validity of the Japanese M-PAS was measured using Spearman's rank correlation coefficients. RESULTS: Cohen's kappa coefficients for the total score and the three domain scores were in the range 0.81-0.98, and 95% confidence intervals included zero for each item, suggesting excellent agreement and no systematic errors. The scores of the Japanese version of M-PAS were significantly correlated with the scores of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale Part II (Spearman's rho=-0.56, P <0.01) and Part III (Spearman's rho=-0.32, P <0.01). The percentage of patients with the highest and the lowest scores in the Japanese version of M-PAS suggested no ceiling or floor effects. CONCLUSION: The Japanese version of M-PAS showed excellent inter-rater reliability and good concurrent validity without ceiling or floor effects.

Deep Vein Thrombosis in Severe Motor and Intellectual Disabilities Patients and Its Treatment by Anticoagulants of Warfarin Versus Edoxaban.

Objective: Patients with severe motor and intellectual disabilities (SMID) often develop complications, including paralysis of the extremities due to abnormal muscular tonicity. Furthermore, the incidence of sudden death, which may be caused by pulmonary thromboembolism (PTE), is approximately 4.2%. Deep vein thrombosis (DVT) is attracting attention as an embolic source. In this study, DVT was confirmed in SMID patients by lower extremity venous ultrasound. The oral anticoagulant, warfarin, and novel oral anticoagulant, edoxaban tosilate hydrate, were administered, and their efficacies and safeties were evaluated. Materials and Methods: DVT patients were randomly allocated to warfarin and edoxaban groups. The frequency of hemorrhagic events and incidence of adverse events were investigated to evaluate efficacy and safety. Results: DVT was detected in 14 (8.4%) out of 167 patients. Four (0.067/person-month) hemorrhagic events occurred in the warfarin group from subcutaneous hemorrhage due to bruises caused by postural changes. Three (0.042/person-month) events occurred in the edoxaban group due to nasal hemorrhage caused by tracheal aspiration. There was no significant difference (p=0.5383) between groups. Conclusion: No significant differences were observed in hemorrhagic events between SMID patients with DVT treated with warfarin and edoxaban.

Multicenter, Open-Label, Randomized Controlled Trial of Warfarin and Edoxaban Tosilate Hydrate for the Treatment of Deep Vein Thrombosis in Persons with Severe Motor Intellectual Disabilities.

Sudden death in patients with severe motor and intellectual disabilities (SMID) is sometimes caused in part by pulmonary thromboembolism (PTE), and deep venous thrombosis (DVT) has drawn attention as a possible embolic source. Warfarin, which is a conventional therapeutic agent, is not easy to control appropriately, and daily management can be especially difficult in SMID patients. On the other hand, edoxaban tosilate hydrate, which has been newly approved for insurance coverage for the treatment of DVT, is not listed in the Guidelines for the Diagnosis, Treatment and Prevention of Pulmonary Thromboembolism and Deep Vein Thrombosis (DVT-PTE guidelines). The aim of this study is to evaluate the efficacy and safety of anticoagulation therapy (warfarin vs. edoxaban) in DVT treatment in SMID patients by means of an open-label, randomized controlled trial. The primary endpoint is the incidence of hemorrhagic events during 12 months of follow up.

Corneal endothelial cells activate innate and acquired arm of anti-viral responses after cytomegalovirus infection.

Infection of the corneal endothelial cells by human cytomegalovirus (CMV) is an important cause of corneal endotheliitis. CMV endotheliitis is difficult to completely cure and relapses are frequent. This can cause blinding corneal bullous keratopathy. However, the pathogenesis of CMV endotheliitis remains undetermined. To understand the immunopathology of endotheliitis, we examined how corneal endothelial cells prime the anti-viral immunity after CMV infection based on global transcriptional responses. To accomplish this, human corneal endothelial (HCEn) cells were infected with CMV, and the global transcriptional responses were determined by microarray analyses for primary anti-viral responses using network analysis. Real-time reverse transcriptase-polymerase chain reaction (RT-PCR) and protein array analyses were used to examine whether anti-viral cytokines were induced, i.e., to determine whether innate immune responses were activated. To examine whether priming of acquired immune response was activated, CMV-infected HCEn cells were co-cultured with allogeneic CD8+ T cells from CMV seropositive donors and tested for priming activity for the CD8+ effector T cells by measuring interferon-γ secretion. The CMV-induced responses of HCEn cells were characterized by type I interferon and pattern recognition receptor pathways which represent innate immune priming. The global transcriptional activation was specifically associated with antigen presentation with the antimicrobial response functions. Protein array analyses indicated a significant increase in the secretion of anti-viral inflammatory cytokines including CXCL10 as innate immune responses. When HCEn cells were examined to determine whether CMV infection activated anti-viral acquired immunity, CMV-infected HCEn cells directly stimulated the proliferation of CD8+ T cells from CMV-seropositive donors, and pp65 viral epitope induced interferon-γ secretion from the CD8+ T cells. We conclude that CMV-infected HCEn cells induce innate immune priming along with provisions of acquired immune priming of CD8+ effector T cells. This information should help in the development of useful diagnostic procedures and efficacious therapeutic strategy to treat refractory corneal endotheliitis.

Blood Pressure Elevation Associated with Topical Prostaglandin F2α Analogs: An Analysis of the Different Spontaneous Adverse Event Report Databases.

Topical prostaglandin F2α (PGF2α) analogs are widely used as the first line of therapy for glaucoma. Systemic PGF2α is suggested to increase blood pressure. Some ophthalmic formulations with ß-receptor blocking or α-receptor stimulating actions are reported to cause systemic adverse events such as a decrease in heart rate and blood pressure. The objective of this study was to evaluate the association between topical PGF2α analogs and blood pressure elevation. We analyzed the reports obtained from the Food and Drug Administration Adverse Event Reporting System (FAERS) database from the first quarter of 2004 until the end of 2015 and the Japanese Adverse Drug Event Report (JADER) database from April 2004 to January 2016 for signal detection using reporting odds ratio (ROR), a method of disproportionality analyses. Signals are considered significant if the ROR estimates and lower bound of the 95% confidence interval (CI) exceed 1. Preferred terms in the Medical Dictionary for Regulatory Activities were utilized to define blood pressure elevation. A total of 6156081 reports from the FAERS and 351226 reports from the JADER were analyzed. The significant RORs with 95% CI were calculated to be 1.82 (95% CI: 1.55-2.13) for bimatoprost, 1.69 (95% CI: 1.53-1.85) for latanoprost, and 2.17 (95% CI: 1.82-2.59) for travoprost from the FAERS. From the JADER, 5.01 (95% CI: 1.59-15.8) was calculated for bimatoprost and 8.02 (95% CI: 2.94-21.9) for tafluprost. The resulting data suggest the necessity for further clinical research on blood pressure elevation associated with topical PGF2α analogs and close monitoring.

The effect of topical application of 0.15% ganciclovir gel on cytomegalovirus corneal endotheliitis.

BACKGROUND/AIMS: The aim of this study was to evaluate the therapeutic efficacy and drug transfer of topical application of 0.15% ganciclovir (GCV) gel on cytomegalovirus (CMV) corneal endotheliitis. METHODS: This study is a multicentre, prospective, interventional case series. Seven eyes of seven immunocompetent patients diagnosed with CMV corneal endotheliitis, based on clinical manifestations and qualitative PCR, were enrolled in this study. The patients were treated with topical applications of 0.15% GCV gel six times daily for 12 weeks without concomitant systemic GCV. Clinical evaluations and quantitative PCR of CMV were performed, and GCV concentrations in aqueous humour were measured by liquid chromatography/tandem mass spectrometry. RESULTS: Clinical improvement of coin-shaped lesions, other types of keratic precipitates, corneal oedema, and anterior chamber inflammation was confirmed at the 4-week visit in all seven eyes. The GCV treatment significantly decreased the CMV copy numbers (p<0.0001). After 12 weeks of treatment, six eyes recovered clear corneas with good vision, and endothelial function was well maintained. Detectable levels of GCV were confirmed in the aqueous humour of all the eyes. The mean GCV concentration in the anterior chamber was 162.0±202.4 ng/mL. The re-emergence of CMV without symptoms was observed in one eye with lower drug transfer. No side effects were observed. CONCLUSIONS: Clinical improvement and reduced CMV copy numbers in the aqueous humour were confirmed in the CMV corneal endotheliitis cases. Although the case numbers are limited and long-term follow-up is necessary, the topical application of 0.15% GCV gel appears to be a useful treatment option for CMV endotheliitis. TRIAL REGISTRATION NUMBER: UMIN000012435.

Systematic Education of Self-Medication at Tokyo University of Pharmacy and Life Sciences.

The promotion of self-medication by pharmacies, with the aim of encouraging a patient's self-selection of proper OTC drug, is written about in the national action plan "Japan is Back". The subject of self-medication has been improved in the 2013 revised edition of "Model Core Curriculum for Pharmaceutical Education". At Tokyo University of Pharmacy and Life Sciences, the systematic education of self-medication was started from the onset of the six-year course in the third, fourth and fifth grade. We introduce here a new approach in our systematic education of self-medication. In the practice of the fourth grade, groups of around 5-6 students are formed. The pharmacy students assume various roles-of pharmacist, rater, observer, and chairman-and perform role-playing. We prepared a standardized patient (SP) showing various symptoms. The student of the role of pharmacist asks about the SP's symptoms, chooses an OTC drug suitable for the SP, and explains the OTC drug to the SP. After the role-playing, those in the roles of rater, observer, SP, and faculty give feedback to the student who played the role of pharmacist. Because we conduct this role-playing using SPs with a variety of symptoms, we can create a situation similar to a real drugstore.

Association between Selective Beta-adrenergic Drugs and Blood Pressure Elevation: Data Mining of the Japanese Adverse Drug Event Report (JADER) Database.

Selective beta-adrenergic drugs are used clinically to treat various diseases. Because of imperfect receptor selectivity, beta-adrenergic drugs cause some adverse drug events by stimulating other adrenergic receptors. To examine the association between selective beta-adrenergic drugs and blood pressure elevation, we reviewed the Japanese Adverse Drug Event Reports (JADERs) submitted to the Japan Pharmaceuticals and Medical Devices Agency. We used the Medical Dictionary for Regulatory Activities (MedDRA) Preferred Terms extracted from Standardized MedDRA queries for hypertension to identify events related to blood pressure elevation. Spontaneous adverse event reports from April 2004 through May 2015 in JADERs, a data mining algorithm, and the reporting odds ratio (ROR) were used for quantitative signal detection, and assessed by the case/non-case method. Safety signals are considered significant if the ROR estimates and lower bound of the 95% confidence interval (CI) exceed 1. A total of 2021 reports were included in this study. Among the nine drugs examined, significant signals were found, based on the 95%CI for salbutamol (ROR: 9.94, 95%CI: 3.09-31.93) and mirabegron (ROR: 7.52, 95%CI: 4.89-11.55). The results of this study indicate that some selective beta-adrenergic drugs are associated with blood pressure elevation. Considering the frequency of their indications, attention should be paid to their use in elderly patients to avoid adverse events.

Characteristic coloring curve for white bread during baking.

The effect of heating conditions on the crust color formation was investigated during the baking of white bread. The surface temperatures were monitored with thermocouples attached to the inside surface of the loaf pan cover. The trace of the surface color in the L(*)a(*)b(*) color coordinate system is defined as the characteristic coloring curve. The overall baking process was classified into the following four stages based on the characteristic coloring curve: i) pre-heating (surface temperature < 110 °C), ii) Maillard reaction (110-150 °C), iii) caramelization (150-200 °C), and iv) over-baking (surface temperature>200 °C). A linear relationship was observed between the L(*) decrease and the increase in weight loss of a sample at each oven air temperature. The L(*) value appeared to be suitable as an indicator to control the surface color by baking conditions.

Odorant transfer characteristics of white bread during baking.

The potent odorants in the crust and crumb of white bread were identified and quantified by gas chromatography-mass spectrometry and gas chromatography/olfactometry. The weight loss ratio of the samples baked at 220 °C was controlled in the range of 0-28%. The odorants were classified into 5 types by the transfer characteristics: i) All amounts of odorant transferred from the crust to external space (type-I). ii) All transferred from the crust to the crumb and external space (type-II). iii) Certain amount remaining in the crust and the rest transferred to the crumb and external space (type-III). iv) All transferred from the crumb to external space (type-IV). v) Certain amount remaining in the crumb and the rest transferred to the crust and external space (type-V). The odorants of type-IV were not apparent after the crust had formed. The results indicate that the crust could be a barrier to prevent the odorants from being transferred to external space.

Ionic liquids of bis(alkylethylenediamine)silver(I) salts and the formation of silver(0) nanoparticles from the ionic liquid system.

We have prepared novel ionic liquids of bis(N-2-ethylhexylethylenediamine)silver(I) nitrate ([Ag(eth-hex-en)(2)]NO(3) and bis(N-hexylethylenediamine)silver(I) hexafluorophosphate ([Ag(hex-en)(2)]PF(6)), which have transition points at -54 and -6 degrees C, respectively. Below these transition temperatures, both the silver complexes assume amorphous states, in which the extent of the vitrification is larger for the eth-hex-en complex than for the hex-en complex. The diffusion coefficients of both the complex cations, measured between 30 (or 35) and 70 degrees C, are largely dependent on temperature; the dependence is particularly large in the case of the eth-hex-en complex cation below 40 degrees C. Small-angle X-ray scattering studies showed that the bilayer structure of the metal complex is formed in the liquid state for both the silver complexes. A direct observation of the yellowish [Ag(eth-hex-en)(2)]NO(3) liquid by transmission electron microscopy (TEM) indicates the presence of nanostructures, as a microemulsion, of less than 5 nm. Such structures were not clearly observed in the [Ag(hex-en)(2)]PF(6) liquid. Although the [Ag(eth-hex-en)(2)]NO(3) liquid is sparingly soluble in bulk water, it readily incorporates a small amount of water up to [water]/[metal complex] = 7:1. Homogeneous and uniformly sized silver(0) nanoparticles in water were created by the reduction of the [Ag(eth-hex-en)(2)]NO(3) liquid with aqueous NaBH(4), whereas silver(0) nanoparticles were not formed from the [Ag(hex-en)(2)]PF(6) liquid in the same way.

Potentiometric and (1)H NMR studies of complexation of Al(3+) with (-)-epigallocatechin gallate, a major active constituent of green tea.

The acid dissociation of (-)-epigallocatechin gallate (abbreviated as egcg) and its complexation with Al(3+) were studied by potentiometric titrations, and were compared with those of (-)-epicatechin (ec) and (-)-epigallocatechin (egc). In Al(3+)-ec and Al(3+)-egc reaction systems, [Al(LH(-2))](+), [Al(LH(-2))(OH)](0), and [Al(LH(-2))(2)](-) are formed, as reported for Al(3+)-catechin (c). Reactions between Al(3+) and egcg at pH <4.1 yield AlLH(-2) and AlLH(-3) species. The 1H NMR studies have shown that two hydroxyl groups of the gallate (D) ring are deprotonated and coordinated to an Al(3+) ion in [Al(egcgH(-2))](+). The AlLH(-3) species of egcg is supposed to be formulated as [Al(egcgH(-3))](0) in which one hydroxyl group of the pyrogallol (B) ring and two hydroxyl groups of the D ring are deprotonated; an Al(3+) ion is coordinated to two oxygen atoms of the D ring and one oxygen atom from the B ring of the neighboring chelate molecule, resulting in the formation of a polymeric structure. In the Al(3+) complex of egcg, the gallate group forms major coordinate bonds and results in solution properties that are different from those of ec, egc and c which have no gallate group.

Binuclear Copper(II) Chelates of Amide-Based Cyclophanes.

A chelating cyclophane has been synthesized by cyclocondensation of two ethylenediaminetetraacetic (EDTA) units with two p-phenylenediamine units: the resulting cyclophane is 2,9,18,25-tetraoxo-4,7,20,23-tetrakis(carboxymethyl)-1,4,7,10,17,20,23,26-octaaza[10.10]paracyclophane, abbreviated as (bis-edtapdn)H(4). Cyclocondensation of two EDTA and two 1,5-diaminonaphthalene units has given the naphthalenophane, 2,9,22,29-tetraoxo-4,7,24,27-tetrakis(carboxymethyl)-1,4,7,10,21,24,27,30-octaaza[10.10](1,5)naphthalenophane, (bis-edtanap)H(4). Studies of electronic and EPR spectra have been carried out on the binuclear Cu(2+) complexes of these new ligands and of related chelating cyclophanes, 2,9,25,32-tetraoxo-4,7,27,30-tetrakis(carboxymethyl)-1,4,7,10,24,27,30,33-octaaza[10.1.10.1]paracyclophane, abbreviated as (bis-edtabpm)H(4), and 2,9,25,32-tetraoxo-4,7,27,30-tetrakis(carboxymethyl)-1,4,7,10,24,27,30,33-octaaza-17,40-dioxa[10.1.10.1]paracyclophane, abbreviated as (bis-edtabpe)H(4). Common features of these chelating cyclophanes are as follows: (1) amino, amide, and pendant carboxymethyl donor groups are substituents in the cyclophane ring, and (2) the amide groups are directly bound to the aromatic groups. These ligands formed neutral binuclear Cu(2+) chelates [Cu(2)L](0) that are water-insoluble. In alkaline solutions, these Cu(2+) complexes were converted to anionic chelates [Cu(2)(LH(-)(4))](4)(-) in which deprotonated amide nitrogens coordinated Cu(2+) ions. These anionic metal chelates of (bis-edtapdn)H(4), (bis-edtabpm)H(4), and (bis-edtabpe)H(4) exhibited three pi-pi transition bands in the spectral range 240-340 nm, in contrast to the uncoordinated cyclophanes, which showed a single band in this spectral range. The unusual pi-pi transition spectra of the [Cu(2)(LH(-)(4))](4)(-) complexes originate from the combined effect of metal-ligand charge transfer and proximity of the pi systems. The absorption and emission spectra of (bis-edtanap)H(4) were also influenced by coordination with copper. The EPR spectrum of [Cu(2)(bis-edtanapH(-)(4))](4)(-) in a methanol glass matrix showed a hyperfine structure due to the spin exchange between two Cu(2+) ions. These unusual spectral and magnetic properties arise from the strong coordination between Cu(2+) ions and deprotonated amide nitrogens that are bound to the pi systems.

A New Chelating Cyclophane and Its Complexation with Ni(2+), Cu(2+), and Zn(2+): Spectroscopic Properties and Allosterism via Ring Contraction.

A condensation reaction between ethylenediaminetetraacetic dianhydride and p-xylenediamine gave a new chelating cyclophane, 3,10,21,28-tetraoxo-5,8,23,26-tetrakis(carboxymethyl)-2,5,8,11,20,23,26,29-octaaza[12.12]paracyclophane, abbreviated as (32edtaxan)H(4), which has three types of electron-donor groups, i.e., amine, carboxylate, and amide groups. The formation of the cyclophane has been confirmed by a single-crystal X-ray analysis of its Zn(2+) complex, [Zn(2)(32edtaxan)].7.5H(2)O, which crystallized in the monoclinic space group P2(1)/c with a = 19.818(1) Å, b = 13.169(1) Å, c = 18.134(1) Å, beta = 104.491(6) degrees, and Z = 4. Each cyclophane molecule coordinates two Zn(2+) ions and results in the formation of a binuclear chelate molecule. The coordination geometry around each metal ion is distorted octahedral, the donor atoms being two carboxylate oxygen atoms, two amine nitrogen atoms, and two amide oxygen atoms. The new cyclophane exhibited a well-defined fluorescence band at 290 nm with 210 nm excitation. The emission intensity was markedly increased in the Zn(2+) complex, in which the coordination of Zn(2+) ions increases the rigidity of the cyclophane leading to a high fluorescence quantum yield. When the cyclophane was coordinated to Cu(2+) ions, the molar absorptivity of a pi-pi transition band observed at 260 nm was increased by a factor of about 10. Such a large spectral change was not observed for the Zn(2+) and Ni(2+) complexes. In the Cu(2+) complex, the two phenyl rings of the cyclophane are expected to be brought closer, as a result of the coordination of deprotonated amide nitrogens to the central metal ion. This allosterism via ring contraction is responsible for the novel behavior of the absorption spectrum. The emission band of the cyclophane was weakened by coordination of copper and nickel as a result of fluorescence quenching caused by a photo-induced electron transfer.