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The detection of small molecules interacting with DNA is important for the assessment of potential hazards related to the application of rather toxic antitumor drugs, and for distinguishing the factors related to thermal and oxidative DNA damage. In this work, a novel electrochemical DNA sensor has been proposed for the determination of antitumor drugs. For DNA sensor assembling, a glassy carbon electrode was modified with carbon black dispersed in DMF. After that, pillar [5]arene was adsorbed and Methylene blue and Neutral red were consecutively electropolymerized onto the carbon black layer. To increase sensitivity of intercalator detection, DNA was first mixed with water-soluble thiacalixarene bearing quaternary ammonium groups in the substituents at the lower rim. The deposition of the mixture on the electropolymerized dyes made it possible to detect doxorubicin as model intercalator by suppression of the redox activity of the polymerization products. The DNA sensor made it possible to determine 0.5 pM–1.0 nM doxorubicin (limit of detection 0.13 pM) with 20 min of incubation. The DNA sensor was successfully tested on spiked samples of human plasma and doxorubicin medication. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.

The elusive monosubstituted diruthenium complexes [Ru2Cl(DAniF)(O2CMe)3] (1), [Ru2Cl(DPhF)(O2CMe)3] (2), [Ru2Cl(D-p-CNPhF)(O2CMe)3] (3), [Ru2Cl(D-o-TolF)(O2CMe)3] (4), [Ru2Cl(D-m-TolF)(O2CMe)3] (5), [Ru2Cl(D-p-TolF)(O2CMe)3] (6) and [Ru2Cl(p-TolA)(O2CMe)3] (7) have been synthesized using for the first time ultrasound-assisted synthesis to carry out a substitution reaction in metal–metal bonded dinuclear compounds (DAniF− = N,N′-bis(4-anisyl)formamidinate; DPhF− = N,N′-diphenylformamidinate; D-p-CNPhF− = N,N′-bis(4-cyanophenyl)formamidinate; D-o/m/p-TolF− = N,N′-bis(2/3/4-tolyl)formamidinate; p-TolA− = N-4-tolylamidate). This is a simpler and greener method than the tedious procedures described in the literature, and it has permitted to obtain water-soluble complexes with good yields in a short period of time. A synthetic study has been implemented to find the best experimental conditions to prepare compounds 1–7. Two different types of ligands, formamidinate and amidate, have been used to check the generality of the method for the preparation of monosubstituted complexes. Five new compounds (2–6) have been obtained using a formamidinate ligand, the synthesis of the previously described compound 1 has been improved, and an unprecedented monoamidate complex has been achieved (7). The crystal structures of compounds 3 and 7 have been solved by single crystal X-ray diffraction. These compounds show the typical paddlewheel structure with three acetate ligands and one formamidinate (3) or amidate (7) bridging ligand at the equatorial positions. The axial positions are occupied by the chloride ligand giving rise to one-dimensional polymer structures that were previously unknown for monosubstituted compounds., Comunidad de Madrid, Depto. de Química Inorgánica, Fac. de Ciencias Químicas, TRUE, pub

OBJECTIVE: To examine associations between diet and risk of developing gastroesophageal reflux disease (GERD). DESIGN: Prospective cohort with a median follow-up of 15.8 years. Baseline diet was measured using a food frequency questionnaire. GERD was defined as self-reported current or history of daily heartburn or acid regurgitation beginning at least two years after baseline. Sex-specific logistic regressions were performed to estimate odds ratios for GERD associated with diet quality scores and intakes of nutrients, food groups, and individual foods and beverages. The effect of substituting saturated fat for monounsaturated or polyunsaturated fat on GERD risk was examined. SETTING: Melbourne, Australia. PARTICIPANTS: A cohort of 20,926 participants (62% women) aged 40-59 years at recruitment between 1990-1994. RESULT(S): For men, total fat intake was associated with increased risk of GERD (OR 1.05 per 5g/d; 95%CI 1.01-1.09; p=0.016), whereas total carbohydrate (OR 0.89 per 30g/d; 95%CI 0.82-0.98; p=0.010) and starch intakes (OR 0.84 per 30g/d; 95%CI 0.75-0.94; p=0.005) were associated with reduced risk. Nutrients were not associated with risk for women. For both sexes, substituting saturated fat for polyunsaturated or monounsaturated fat did not change risk. For both sexes, fish, chicken, cruciferous vegetables, and carbonated beverages were associated with increased risk, whereas total fruit and citrus were associated with reduced risk. No association was observed with diet quality scores. CONCLUSION(S): Diet is a possible risk factor for GERD, but food considered as triggers of GERD symptoms might not necessarily contribute to disease development. Potential differential associations for men and women warrant further investigation.

OBJECTIVE: To examine associations between diet and risk of developing gastroesophageal reflux disease (GERD). DESIGN: Prospective cohort with a median follow-up of 15.8 years. Baseline diet was measured using a food frequency questionnaire. GERD was defined as self-reported current or history of daily heartburn or acid regurgitation beginning at least two years after baseline. Sex-specific logistic regressions were performed to estimate odds ratios for GERD associated with diet quality scores and intakes of nutrients, food groups, and individual foods and beverages. The effect of substituting saturated fat for monounsaturated or polyunsaturated fat on GERD risk was examined. SETTING: Melbourne, Australia. PARTICIPANTS: A cohort of 20,926 participants (62% women) aged 40-59 years at recruitment between 1990-1994. RESULT(S): For men, total fat intake was associated with increased risk of GERD (OR 1.05 per 5g/d; 95%CI 1.01-1.09; p=0.016), whereas total carbohydrate (OR 0.89 per 30g/d; 95%CI 0.82-0.98; p=0.010) and starch intakes (OR 0.84 per 30g/d; 95%CI 0.75-0.94; p=0.005) were associated with reduced risk. Nutrients were not associated with risk for women. For both sexes, substituting saturated fat for polyunsaturated or monounsaturated fat did not change risk. For both sexes, fish, chicken, cruciferous vegetables, and carbonated beverages were associated with increased risk, whereas total fruit and citrus were associated with reduced risk. No association was observed with diet quality scores. CONCLUSION(S): Diet is a possible risk factor for GERD, but food considered as triggers of GERD symptoms might not necessarily contribute to disease development. Potential differential associations for men and women warrant further investigation.

N-Methylpyrrolidone is one of several chemotypes that have been described as a mimetic of acetyl-lysine in the development of bromodomain inhibitors. In this paper, we describe the synthesis of a 4-phenyl substituted analogue - 1-methyl-4-phenylpyrrolidin-2-one - and the use of aryl substitution reactions as a divergent route for derivatives. Ultimately, this has led to structurally complex, chiral compounds with progressively improved affinity as inhibitors of bromodomain-containing protein 4.Copyright © 2020 Elsevier Masson SAS

N-Methylpyrrolidone is one of several chemotypes that have been described as a mimetic of acetyl-lysine in the development of bromodomain inhibitors. In this paper, we describe the synthesis of a 4-phenyl substituted analogue - 1-methyl-4-phenylpyrrolidin-2-one - and the use of aryl substitution reactions as a divergent route for derivatives. Ultimately, this has led to structurally complex, chiral compounds with progressively improved affinity as inhibitors of bromodomain-containing protein 4.Copyright © 2020 Elsevier Masson SAS

Objective: High-anion gap metabolic acidosis (HAGMA) most commonly results from excess urea, lactate, ketones and exposure to toxins such as salicylate and toxic alcohols. Accumulation of pyroglutamic acid (PGA) is a rare cause of HAGMA. The exact incidence of HAGMA caused by PGA accumulation is unknown. A recent prospective study reported that high urine PGA concentrations were associated with 10% of patients with HAGMA. PGA is processed by the glutamate-glutathione cycle. The commonest cause of PGA accumulation is glutathione depletion. This causes the loss of negative feedback on gamma-glutamylcysteine (PGA precursor) production. Other causes include malnutrition, alcoholism, liver failure and sepsis. Though rare, deficiency of either glutathione synthetase causing gamma-glutamylcysteine (PGA precursor) accumulation or 5-oxoprolinase resulting in reduced PGA metabolism, also cause PGA accumulation. We describe a case of confirmed PGA accumulation after repeated supratherapeutic paracetamol use. Case report: A 32-year-old female presented with ongoing pain from shingles despite having taken 96 x 665 mg modified-release paracetamol caplets over the preceding two days. Two years prior, she suffered a gastric ulcer perforation following excessive ibuprofen use for dysmenorrhea. She subsequently ceased using NSAIDs and substituted these with regular use of four modifiedrelease paracetamol tablets every 3-4 hours. On presentation vital signs were normal except a respiratory rate of 24/min. Venous blood gas showed pH 7.04, bicarbonate 5.0mmol/L, pCO2 19 mmHg, lactate 1.4mmol/L, sodium 150mmol/L, chloride 117 mmol/L and anion gap 28, indicating a partially compensated HAGMA. Serum ketones were 2.8mmol/L, salicylate undetected and normal osmolar gap. Serum paracetamol was 312 mumol/L, 2.5 hours after the last dose. Liver function, INR and creatinine were normal. PGA accumulation from chronic paracetamol misuse and glutathione depletion was suspected. Acetylcysteine was in

A series of N-substituted maleimide derivatives have been developed via acetic acid-mediated microwave reaction pathway, which was identified as the incomparable method for this maleimide compounds. All the synthesized compounds were tested for antioxidant activity by DPPH and H 2 O 2 methods. Compounds 5h and 5m were displayed with higher antioxidant activity in two methods. The structure–activity relationship demonstrated that the compounds having electron releasing substitutions 5h and 5m generally show beneficial activity than electron capture substitution cores. Thus, compounds 5h and 5m may be useful as an exogenous antioxidant. © 2018 Wiley Periodicals, Inc.

The substitution reactions of a NO-ligated dinuclear ruthenium complex with ammonium thiocyanate (NH4SCN), sulfur, and dimethyl sulfoxide (DMSO) gave the corresponding mononitrosyl dinuclear complexes, except for reaction with sulfur, where diastereomers of a S2-bridged tetranuclear complex along with a NO- and S2-bridged dinuclear complex were obtained. According to the scan rate dependent cyclic voltammograms, linkage isomerism of a dmso ligand on the dinuclear complex was revealed, and the linkage isomer was obtained from the chemical oxidation., Inorganica Chimica Acta, 490, pp.45-50; 2019

Aims. Biosimilars are being adopted in Australia and worldwide to improve affordability and access to treatment. Current literature has focussed on physicians' confidence in biosimilars. An effective introduc-tion of biosimilars requires an understanding of patient acceptance of these agents. This study aims to investigate patient awareness and attitudes to biosimilar medicine in a tertiary hospital RA clinic. Methods. A cross-sectional study of 127 patients with RA was performed. A brief education on biosimilars was provided. Patients rated concerns regarding biosimilar efficacy, side-effects and general concerns on a ten-point scale. Results. 45.2% of our cohort have received biological DMARDs. Only 5.6% have some knowledge of biosimilars, 75.4% would accept biosimilars if their rheumatologist recommends it, with only 5.6% refusing to switch. 19% of patients were unsure. Of those refusing biosimilars, the main concerns related to efficacy and general concerns about change. In our RA cohort, 61.9% took generic medicines regularly and 84.6% of these would also be comfortable taking biosimilars. In those refusing generic medicines (27%), 61.8% would be still comfortable taking biosimilars. 15.9% and 12.7% of patients had great concerns about the efficacy and safety profile of biosimilars, respectively. 26.2% were worried that their physician may be unaware if they were receiving the biosimilar or reference product. Conclusion. Despite being unfamiliar with biosimilars, most patients in our cohort would be comfortable taking biosimilars if recommended by their rheumatologist, highlighting the role of trust in doctor-patient rela-tionships. Of patients usually refusing generic medicines, nearly two-thirds would still accept biosimilars. Australian pharmacists can substitute biological DMARDs without informing the prescriber. This concerns pre-scribers in Australia and overseas (88-95%). The majority of patients in our study were not concerned, whilst approximately one

Background: Advancement in biological disease-modifying antirheumatic drugs (bDMARDs) has greatly improved the prognosis of patients with rheumatoid arthritis. Their high costs, however, pose a significant health-economic challenge. Biosimilars are being adopted in Australia and worldwide to improve affordability and access to treatment. While the predominant focus of current literature has been on physicians' awareness and confidence of biosimilars, an effective introduction of biosimilars requires an understanding of patient acceptance of these products. Objective(s): To investigate patient awareness and attitudes to biosimilar medicine in a tertiary hospital RA clinic. Method(s): A cross-sectional study of 127 patients with rheumatoid arthritis was performed in Melbourne, Australia. A brief education on biosimilars was provided. Patients rated concerns regarding biosimilar efficacy, side-effect profile, operation of the medication, and general attitude towards the new medication on a ten-point scale. (Figure Presented) Results: 45.2% of our cohort have received biological DMARDs. Although only 5.6% have some knowledge of biosimilars, 75.4% would accept biosimilars if their rheumatologist recommends it, with only 5.6% refusing to switch. 19% of patients were unsure. Of those refusing biosimilars, the main concerns related to efficacy and general concerns about change. In our RA cohort, 61.9% took generic medicines regularly and 84.6% of these they would also be comfortable taking biosimilars. In those refusing generic medicines (27%), 61.8% would be still comfortable taking biosimilars. 15.9% and 12.7% of patients had great concerns about the efficacy and safety profile of biosimilars, respectively. 26.2% were significantly worried that their physician may be unaware if they were receiving the biosimilar or reference product. Conclusion(s): Despite being unfamiliar with biosimilars, most patients in our cohort would be comfortable taking biosimilars if recommended

Background and Aims: Limited data on the long-term persistence of NS5A and NS3 HCV resistance associated substitutions (RASs) are available after treatment with clinically relevant HCV regimens. The aim of this study was to evaluate the persistence of NS3, NS5A and NS5B nucleotide inhibitor (NI) RASs in patients not achieving SVR in Gilead-sponsored treatment studies who were enrolled in a followup Sequence Registry. Method(s): Patients who did not achieve SVR following treatment with a DAA-containing regimen in a Gilead treatment protocol were eligible for enrollment into the Sequence Registry where they were followed for up to an additional 144 weeks. Patients had NS5A, NS3 and/or NS5B regions sequenced if they were exposed to an NSS5A inhibitor (ledipasvir [LDV] or velpatasvir [VEL]), an NS3 inhibitor (vedroprevir [VDV] or voxilaprevir [VOX]), and/or an NS5B NI (sofosbuvir [SOF]), respectively. Patients were discontinued if they received HCV treatment or once RASs were no longer detectable. Results are reported using a 15% cutoff. Result(s): Treatment-emergent NS5A and NS3 RASs were observed at the time of virologic failure (VF) in 95% and 93% of registry enrolled patients treated with non-SOF based regimens, respectively. NS5A and NS3 RASs were present at Week 144 in 63% and 25% of non-SOF treated patients, respectively. Treatment-emergent NS5A resistance was observed in 48% of registry enrolled patients at the time of VF with a SOF-based regimen. No treatment-emergent NS3 RASs were detected among the SOF/VEL/VOX failures enrolled in the study (Table). More than 1 NS5A RAS was detected in 47% and 7% of patients treated with non-SOF and SOF-based regimens, respectively. Treatment-emergent NS5B NI RASs were observed in 13/227 (6%) patients treated with a SOF-based regimens at the time of VF. No S282T was observed in any patient. Conclusion(s): Among patients enrolled in this follow up registry, treatment-emergent RASs at the time of VF as well as long-term persist

Aims. Biosimilars are being adopted in Australia and worldwide to improve affordability and access to treatment. Current literature has focussed on physicians' confidence in biosimilars. An effective introduc-tion of biosimilars requires an understanding of patient acceptance of these agents. This study aims to investigate patient awareness and attitudes to biosimilar medicine in a tertiary hospital RA clinic. Methods. A cross-sectional study of 127 patients with RA was performed. A brief education on biosimilars was provided. Patients rated concerns regarding biosimilar efficacy, side-effects and general concerns on a ten-point scale. Results. 45.2% of our cohort have received biological DMARDs. Only 5.6% have some knowledge of biosimilars, 75.4% would accept biosimilars if their rheumatologist recommends it, with only 5.6% refusing to switch. 19% of patients were unsure. Of those refusing biosimilars, the main concerns related to efficacy and general concerns about change. In our RA cohort, 61.9% took generic medicines regularly and 84.6% of these would also be comfortable taking biosimilars. In those refusing generic medicines (27%), 61.8% would be still comfortable taking biosimilars. 15.9% and 12.7% of patients had great concerns about the efficacy and safety profile of biosimilars, respectively. 26.2% were worried that their physician may be unaware if they were receiving the biosimilar or reference product. Conclusion. Despite being unfamiliar with biosimilars, most patients in our cohort would be comfortable taking biosimilars if recommended by their rheumatologist, highlighting the role of trust in doctor-patient rela-tionships. Of patients usually refusing generic medicines, nearly two-thirds would still accept biosimilars. Australian pharmacists can substitute biological DMARDs without informing the prescriber. This concerns pre-scribers in Australia and overseas (88-95%). The majority of patients in our study were not concerned, whilst approximately one

Background: Advancement in biological disease-modifying antirheumatic drugs (bDMARDs) has greatly improved the prognosis of patients with rheumatoid arthritis. Their high costs, however, pose a significant health-economic challenge. Biosimilars are being adopted in Australia and worldwide to improve affordability and access to treatment. While the predominant focus of current literature has been on physicians' awareness and confidence of biosimilars, an effective introduction of biosimilars requires an understanding of patient acceptance of these products. Objective(s): To investigate patient awareness and attitudes to biosimilar medicine in a tertiary hospital RA clinic. Method(s): A cross-sectional study of 127 patients with rheumatoid arthritis was performed in Melbourne, Australia. A brief education on biosimilars was provided. Patients rated concerns regarding biosimilar efficacy, side-effect profile, operation of the medication, and general attitude towards the new medication on a ten-point scale. (Figure Presented) Results: 45.2% of our cohort have received biological DMARDs. Although only 5.6% have some knowledge of biosimilars, 75.4% would accept biosimilars if their rheumatologist recommends it, with only 5.6% refusing to switch. 19% of patients were unsure. Of those refusing biosimilars, the main concerns related to efficacy and general concerns about change. In our RA cohort, 61.9% took generic medicines regularly and 84.6% of these they would also be comfortable taking biosimilars. In those refusing generic medicines (27%), 61.8% would be still comfortable taking biosimilars. 15.9% and 12.7% of patients had great concerns about the efficacy and safety profile of biosimilars, respectively. 26.2% were significantly worried that their physician may be unaware if they were receiving the biosimilar or reference product. Conclusion(s): Despite being unfamiliar with biosimilars, most patients in our cohort would be comfortable taking biosimilars if recommended

Background and Aims: Limited data on the long-term persistence of NS5A and NS3 HCV resistance associated substitutions (RASs) are available after treatment with clinically relevant HCV regimens. The aim of this study was to evaluate the persistence of NS3, NS5A and NS5B nucleotide inhibitor (NI) RASs in patients not achieving SVR in Gilead-sponsored treatment studies who were enrolled in a followup Sequence Registry. Method(s): Patients who did not achieve SVR following treatment with a DAA-containing regimen in a Gilead treatment protocol were eligible for enrollment into the Sequence Registry where they were followed for up to an additional 144 weeks. Patients had NS5A, NS3 and/or NS5B regions sequenced if they were exposed to an NSS5A inhibitor (ledipasvir [LDV] or velpatasvir [VEL]), an NS3 inhibitor (vedroprevir [VDV] or voxilaprevir [VOX]), and/or an NS5B NI (sofosbuvir [SOF]), respectively. Patients were discontinued if they received HCV treatment or once RASs were no longer detectable. Results are reported using a 15% cutoff. Result(s): Treatment-emergent NS5A and NS3 RASs were observed at the time of virologic failure (VF) in 95% and 93% of registry enrolled patients treated with non-SOF based regimens, respectively. NS5A and NS3 RASs were present at Week 144 in 63% and 25% of non-SOF treated patients, respectively. Treatment-emergent NS5A resistance was observed in 48% of registry enrolled patients at the time of VF with a SOF-based regimen. No treatment-emergent NS3 RASs were detected among the SOF/VEL/VOX failures enrolled in the study (Table). More than 1 NS5A RAS was detected in 47% and 7% of patients treated with non-SOF and SOF-based regimens, respectively. Treatment-emergent NS5B NI RASs were observed in 13/227 (6%) patients treated with a SOF-based regimens at the time of VF. No S282T was observed in any patient. Conclusion(s): Among patients enrolled in this follow up registry, treatment-emergent RASs at the time of VF as well as long-term persist

Despite the fact that the transition structure of the gas phase SN2 reaction H2O + HOOH2+ → HOOH2+ + H2O is well below the reactants in potential energy, the reaction has not yet been obsd. by expt. Variational transition state RRKM theory reveals a strong preference for the competing proton transfer reaction H2O + HOOH2+ → H3O+ + HOOH due to entropy factors. Born-Oppenheimer reaction dynamics simulations confirm these results. However, by increasing the collision energy to around 7.5 eV the probability for nucleophilic substitution increases relative to proton transfer. These observations are explained by the presence of the key common intermediate HOO(H)···H-OH2+ which leads to effective proton transfer, but can be avoided with increasing collision energy. However, the SN2 probability remains below 0.2 since successful passage through the TS requires optimum initial orientation of the reactants, excitation of the relative translational motion and good phase correlation between the O-O vibration and the motion of the incoming water.

Despite the fact that the transition structure of the gas phase SN2 reaction H2O + HOOH2+ → HOOH2+ + H2O is well below the reactants in potential energy, the reaction has not yet been obsd. by expt. Variational transition state RRKM theory reveals a strong preference for the competing proton transfer reaction H2O + HOOH2+ → H3O+ + HOOH due to entropy factors. Born-Oppenheimer reaction dynamics simulations confirm these results. However, by increasing the collision energy to around 7.5 eV the probability for nucleophilic substitution increases relative to proton transfer. These observations are explained by the presence of the key common intermediate HOO(H)···H-OH2+ which leads to effective proton transfer, but can be avoided with increasing collision energy. However, the SN2 probability remains below 0.2 since successful passage through the TS requires optimum initial orientation of the reactants, excitation of the relative translational motion and good phase correlation between the O-O vibration and the motion of the incoming water.

A series of PI3Kdelta inhibitors derived from the pan-PI3K inhibitor ZSTK474 was prepared that target a non-conserved region of the catalytic site. Dependent upon the substituents present, these analogues show different levels of isoform selectivity and sensitivity to the mutation N836D in PI3Kdelta. As a marker of 'on-target' activity and permeability, a selection of the most potent PI3Kdelta inhibitors were shown to inhibit pAkt production in the Nawalma Burkitt lymphoma cell line.Copyright © 2016 Elsevier Ltd

A series of PI3Kdelta inhibitors derived from the pan-PI3K inhibitor ZSTK474 was prepared that target a non-conserved region of the catalytic site. Dependent upon the substituents present, these analogues show different levels of isoform selectivity and sensitivity to the mutation N836D in PI3Kdelta. As a marker of 'on-target' activity and permeability, a selection of the most potent PI3Kdelta inhibitors were shown to inhibit pAkt production in the Nawalma Burkitt lymphoma cell line.Copyright © 2016 Elsevier Ltd

Well-defined cellulose-graft-polyacrylamide copolymers were synthesized in a grafting-from approach by reversible addition-fragmentation chain transfer polymerization (RAFT). A chlorine moiety (degree of substitution DS(Cl) ≈ 1.0) was introduced into the cellulose using 1-butyl-3-methylimidazolium chloride (BMIMCl) as solvent before being substituted by a trithiocarbonate moiety resulting in cellulose macro-chain transfer agents (cellulose-CTA) with DS(RAFT) of 0.26 and 0.41. Poly(N,N-diethylacrylamide) (PDEAAm) and poly(N-isopropylacrylamide) (PNIPAM) were subsequently grafted from these cellulose-CTAs and the polymerization kinetics, the molecular weight characteristics and the product composition were studied by nuclear magnetic resonance spectroscopy, X-ray photoelectron spectroscopy, and size exclusion chromatography of the polyacrylamides after cleavage from the cellulose chains. The number-average molecular weights, Mn, of the cleaved polymers ranged from 1100 to 1600 g mol-1 for PDEAAm (dispersity D = 1.4-1.8) and from 1200 to 2600 g mol -1 for PNIPAM (D = 1.7-2.1). The LCST behavior of the cellulose-graft-copolymers was studied via the determination of cloud point temperatures, evidencing that the thermoresponsive properties of the hybrid materials could be finely tuned between 18 and 26 °C for PDEAAm and between 22 and 26 °C for PNIPAM side chains. © 2014 American Chemical Society.

A three-component reaction of 3-substituted coumarins with N-alkyl-α-amino acids and aldehydes gave 1-benzopyrano[3,4-c]pyrrolidines as a result of a 1,3-dipolar cycloaddition of an intermediate nonstabilized azomethine ylide at the double bond of the coumarin system in moderate to good yields. In most cases, high regio- and stereo-selectivity of the [3+2] cycloaddition was observed. © 2013 Elsevier Ltd. All rights reserved.

5-Bromopyrimidine reacts with 2,2′-bithiophene, [2,2′:5′, 2″]terthiophene and 2-phenylthiophene in the presence of a palladium catalyst to give 5-(het)aryl substituted pyrimidines due to the palladium-catalyzed aryl-aryl C-C coupling. However 5-bromo-4-(het)aryl- pyrimidines have been prepared from the same starting materials through the SN H-reaction catalyzed by a Lewis acid. Conditions for both types of reactions were optimized. All components of the reaction mixtures, including by-products, have been elucidated by gas-liquid chromatography/mass- spectrometry. Evidence for the structure of 4- and 5-bithiophenyl-substituted pyrimidines has first been obtained by means of X-ray crystallography analysis. Molecular orbital calculations (TDDFT), as well as the redox and optical measurements for all new compounds have also been performed. © 2013 Elsevier Ltd. All rights reserved.

Organosilicon-mediated, regioselective acetylation of vicinal- and 1,3-diols is presented. Methyl trimethoxysilane or dimethyl dimethoxysilane was first used to form cyclic 1,3,2-dioxasilolane or 1,3,2-dioxasilinane intermediates, and subsequent acetate-catalyzed monoacylation was efficiently performed by addition of acetic anhydride or acetyl chloride under mild conditions. The reaction exhibited high regioselectivity, resulting in the same protection pattern as in organotin-mediated schemes., QC 20120803

Antibodies empower numerous important scientific, clinical, diagnostic, and industrial applications. Ideally, the epitope(s) targeted by an antibody should be identified and characterized, thereby establishing antibody reactivity, highlighting possible cross-reactivities, and perhaps even warning against unwanted (e.g. autoimmune) reactivities. Antibodies target proteins as either conformational or linear epitopes. The latter are typically probed with peptides, but the cost of peptide screening programs tends to prohibit comprehensive specificity analysis. To perform high-throughput, high-resolution mapping of linear antibody epitopes, we have used ultrahigh-density peptide microarrays generating several hundred thousand different peptides per array. Using exhaustive length and substitution analysis, we have successfully examined the specificity of a panel of polyclonal antibodies raised against linear epitopes of the human proteome and obtained very detailed descriptions of the involved specificities. The epitopes identified ranged from 4 to 12 amino acids in size. In general, the antibodies were of exquisite specificity, frequently disallowing even single conservative substitutions. In several cases, multiple distinct epitopes could be identified for the same target protein, suggesting an efficient approach to the generation of paired antibodies. Two alternative epitope mapping approaches identified similar, although not necessarily identical, epitopes. These results show that ultrahigh-density peptide microarrays can be used for linear epitope mapping. With an upper theoretical limit of 2,000,000 individual peptides per array, these peptide microarrays may even be used for a systematic validation of antibodies at the proteomic level., QC 20130111

Two series of amino-substituted 1,2,4- and 1,3,4-oxadiazole matched compounds were evaluated and found to have significant differences in their various physical and pharmaceutical properties. Experimental and computational techniques suggested that variation in hydrogen bond acceptor and donor strength were responsible for these effects., QC 20120619

Biodegradable scaffolds serve a central role for tissue engineering scaffolds and guiding tissue regeneration. Some of these scaffolds, including apatites, display a significant effect upon cell adhesion and cell proliferation. The incorporation of scaffold technology with the developing embryonic stem (ES) cell field and the capacity of ES cells for self-renewal and differentiation are believed to hold enormous potential for applications in biomedical research and regenerative medicine. The purpose of this work was to determine the effect of hydroxyapatite (HAP) and fluoride substitutions of HAP upon ES cell growth and colonisation. Sintered hydroxyfluorapatite discs were found to support cellular proliferation and colonisation, and the ES cells displayed a tendency for differentiation on the apatite surface as determined by reductions in colony Oct4 immunoreactivity. Fluoride-containing HAPs were found to provide equivalent support to gelatin in terms of cell numbers, yet superior support for cellular colonisation when compared to HAP. This study indicates that fluoride substitutions of HAP may represent a viable strategy for the development of certain engineered tissue replacements and tissue regeneration systems using ES cells. © 2004 Elsevier Ltd. All rights reserved.

Three isomers of chloro-3-(2-pyridin-3-ylvinyl)-1H-indole were synthesized and tested as inhibitors of human tryptophan 2,3-dioxygenase (hTDO). The crystal structures of two of them were solved by X-ray diffraction. The solubility of the molecules also was determined experimentally. The molecular electrostatic potentials and dipole moments of the three isomers were calculated by ab initio quantum mechanics (HF/6-311G). The single crystal X-ray analyses reveal non-planar structures. This non-coplanarity is retained during docking of the compounds into a model of hTDO, the molecular target of this series. The position of the Cl atom does not significantly affect the electronic delocalization. Nevertheless, the position of the Cl atom produces a local variation of bond lengths inducing different dipole moments for these isomers. Variations in dipole moments are consistent with the different melting points and crystal packings. Differences in aqueous solubilities are best explained by subtle changes in H-bonds resulting from different accessibilities of the indole NH's due to steric effects of the Cl substituent. The non-coplanarity plays an important role in the crystalline packing of the molecules in contrast to the position of the Cl. This study leads to a better understanding of the structural and electronic characteristics of this chemical series and can potentially help to better understand their inhibitory activity. © 2012 Elsevier Masson SAS. All rights reserved.

Three isomers of chloro-3-(2-pyridin-3-ylvinyl)-1H-indole were synthesized and tested as inhibitors of human tryptophan 2,3-dioxygenase (hTDO). The crystal structures of two of them were solved by X-ray diffraction. The solubility of the molecules also was determined experimentally. The molecular electrostatic potentials and dipole moments of the three isomers were calculated by ab initio quantum mechanics (HF/6-311G). The single crystal X-ray analyses reveal non-planar structures. This non-coplanarity is retained during docking of the compounds into a model of hTDO, the molecular target of this series. The position of the Cl atom does not significantly affect the electronic delocalization. Nevertheless, the position of the Cl atom produces a local variation of bond lengths inducing different dipole moments for these isomers. Variations in dipole moments are consistent with the different melting points and crystal packings. Differences in aqueous solubilities are best explained by subtle changes in H-bonds resulting from different accessibilities of the indole NH's due to steric effects of the Cl substituent. The non-coplanarity plays an important role in the crystalline packing of the molecules in contrast to the position of the Cl. This study leads to a better understanding of the structural and electronic characteristics of this chemical series and can potentially help to better understand their inhibitory activity. © 2012 Elsevier Masson SAS. All rights reserved.

Biodegradable scaffolds serve a central role for tissue engineering scaffolds and guiding tissue regeneration. Some of these scaffolds, including apatites, display a significant effect upon cell adhesion and cell proliferation. The incorporation of scaffold technology with the developing embryonic stem (ES) cell field and the capacity of ES cells for self-renewal and differentiation are believed to hold enormous potential for applications in biomedical research and regenerative medicine. The purpose of this work was to determine the effect of hydroxyapatite (HAP) and fluoride substitutions of HAP upon ES cell growth and colonisation. Sintered hydroxyfluorapatite discs were found to support cellular proliferation and colonisation, and the ES cells displayed a tendency for differentiation on the apatite surface as determined by reductions in colony Oct4 immunoreactivity. Fluoride-containing HAPs were found to provide equivalent support to gelatin in terms of cell numbers, yet superior support for cellular colonisation when compared to HAP. This study indicates that fluoride substitutions of HAP may represent a viable strategy for the development of certain engineered tissue replacements and tissue regeneration systems using ES cells. © 2004 Elsevier Ltd. All rights reserved.

A series of 8-phenylaminopyrimido[4,5-c]isoquinoline-7,10-quinone derivatives were prepared by regioselective amination reaction of pyrimido[4,5-c] isoquinoline-7,10-quinones with arylamines in the presence of a Lewis acid catalyst. Preliminary evaluation of the members of the series against cancer cell lines and assays of activation of their cytotoxic activity on K562 cells with ascorbic acid are reported. (C) 2009 Elsevier Ltd. All rights reserved.

The serendipitous discovery of the potent cytotoxic properties of cisplatin brought about a revolution in the treatment of certain types of cancer, but almost fifty years later, there still remain unknown areas in the chemistry of cisplatin. There are questions regarding which form of the drug reaches its DNA target, or why certain DNA sequences are more preferred than others for reaction with cisplatin. The work presented here aims to address some of these problems, using quantum chemical calculations to complement and interpret available experimental data. Cisplatin's activation reactions are explored by Density Functional Theory (DFT) on two model systems, one solely using a self-consistent reaction field (SCRF) for modeling bulk water, and one including an additional partial solvation shell of water molecules. It is concluded that adding explicit solvation provides a better picture than using SCRF solvation alone. The energy surface supports the view that the active form of cisplatin is the monoaquated form. The activation reactions of the cisplatin-derived drug, JM118, are investigated using DFT and SCRF calculations using three solvation model systems. The results show a slower rate of hydrolysis for the first reaction, and a faster rate for the second, suggesting diaquated JM118 as the main DNA binding form of the drug. Diaquated cisplatin's first and second reaction with guanine and adenine are studied using DFT and SCRF solvation. Cisplatin's propensity toward guanine in the first substitution is explained by larger stabilisation energy for the initially formed complex and by favoured kinetics. For the second substitution, higher stability in complexation with guanine over adenine is ascribed as the main factor favouring guanine over adenine substitution. This provides the first explanation for the predominance of 1,2-d(GpG) over 1,2-d(ApG) adducts, and the direction specificity of the 1,2-d(ApG) adducts.

The serendipitous discovery of the potent cytotoxic properties of cisplatin brought about a revolution in the treatment of certain types of cancer, but almost fifty years later, there still remain unknown areas in the chemistry of cisplatin. There are questions regarding which form of the drug reaches its DNA target, or why certain DNA sequences are more preferred than others for reaction with cisplatin. The work presented here aims to address some of these problems, using quantum chemical calculations to complement and interpret available experimental data. Cisplatin's activation reactions are explored by Density Functional Theory (DFT) on two model systems, one solely using a self-consistent reaction field (SCRF) for modeling bulk water, and one including an additional partial solvation shell of water molecules. It is concluded that adding explicit solvation provides a better picture than using SCRF solvation alone. The energy surface supports the view that the active form of cisplatin is the monoaquated form. The activation reactions of the cisplatin-derived drug, JM118, are investigated using DFT and SCRF calculations using three solvation model systems. The results show a slower rate of hydrolysis for the first reaction, and a faster rate for the second, suggesting diaquated JM118 as the main DNA binding form of the drug. Diaquated cisplatin's first and second reaction with guanine and adenine are studied using DFT and SCRF solvation. Cisplatin's propensity toward guanine in the first substitution is explained by larger stabilisation energy for the initially formed complex and by favoured kinetics. For the second substitution, higher stability in complexation with guanine over adenine is ascribed as the main factor favouring guanine over adenine substitution. This provides the first explanation for the predominance of 1,2-d(GpG) over 1,2-d(ApG) adducts, and the direction specificity of the 1,2-d(ApG) adducts.

The serendipitous discovery of the potent cytotoxic properties of cisplatin brought about a revolution in the treatment of certain types of cancer, but almost fifty years later, there still remain unknown areas in the chemistry of cisplatin. There are questions regarding which form of the drug reaches its DNA target, or why certain DNA sequences are more preferred than others for reaction with cisplatin. The work presented here aims to address some of these problems, using quantum chemical calculations to complement and interpret available experimental data. Cisplatin's activation reactions are explored by Density Functional Theory (DFT) on two model systems, one solely using a self-consistent reaction field (SCRF) for modeling bulk water, and one including an additional partial solvation shell of water molecules. It is concluded that adding explicit solvation provides a better picture than using SCRF solvation alone. The energy surface supports the view that the active form of cisplatin is the monoaquated form. The activation reactions of the cisplatin-derived drug, JM118, are investigated using DFT and SCRF calculations using three solvation model systems. The results show a slower rate of hydrolysis for the first reaction, and a faster rate for the second, suggesting diaquated JM118 as the main DNA binding form of the drug. Diaquated cisplatin's first and second reaction with guanine and adenine are studied using DFT and SCRF solvation. Cisplatin's propensity toward guanine in the first substitution is explained by larger stabilisation energy for the initially formed complex and by favoured kinetics. For the second substitution, higher stability in complexation with guanine over adenine is ascribed as the main factor favouring guanine over adenine substitution. This provides the first explanation for the predominance of 1,2-d(GpG) over 1,2-d(ApG) adducts, and the direction specificity of the 1,2-d(ApG) adducts.

The serendipitous discovery of the potent cytotoxic properties of cisplatin brought about a revolution in the treatment of certain types of cancer, but almost fifty years later, there still remain unknown areas in the chemistry of cisplatin. There are questions regarding which form of the drug reaches its DNA target, or why certain DNA sequences are more preferred than others for reaction with cisplatin. The work presented here aims to address some of these problems, using quantum chemical calculations to complement and interpret available experimental data. Cisplatin's activation reactions are explored by Density Functional Theory (DFT) on two model systems, one solely using a self-consistent reaction field (SCRF) for modeling bulk water, and one including an additional partial solvation shell of water molecules. It is concluded that adding explicit solvation provides a better picture than using SCRF solvation alone. The energy surface supports the view that the active form of cisplatin is the monoaquated form. The activation reactions of the cisplatin-derived drug, JM118, are investigated using DFT and SCRF calculations using three solvation model systems. The results show a slower rate of hydrolysis for the first reaction, and a faster rate for the second, suggesting diaquated JM118 as the main DNA binding form of the drug. Diaquated cisplatin's first and second reaction with guanine and adenine are studied using DFT and SCRF solvation. Cisplatin's propensity toward guanine in the first substitution is explained by larger stabilisation energy for the initially formed complex and by favoured kinetics. For the second substitution, higher stability in complexation with guanine over adenine is ascribed as the main factor favouring guanine over adenine substitution. This provides the first explanation for the predominance of 1,2-d(GpG) over 1,2-d(ApG) adducts, and the direction specificity of the 1,2-d(ApG) adducts.

The poly(styrene)-block-poly(2-vinylpyridine)-block-poly(ethylene oxide) triblock copolymer PS 200-b-P2VP 140-b-PEO 590, where the subscripts refer to the number average degrees of polymerization, forms spherical micelles in water, that consist of a PS core, a pH-responsive P2VP shell and a PEO corona. This triblock has been added with homo-PS before micellization in order to increase the volume fraction of the core-forming block. The length of the added homo-PS has been varied with respect to the length of the PS core-forming block: much shorter, much longer and approximately the same. The structure of the micelles has been investigated by transmission electron microscopy, static and dynamic light scattering. Homo-PS phase separates whenever its length is larger than the one of the PS core-forming chains; otherwise this phenomenon occurs beyond a critical concentration that depends on molecular weight. The addition of homo-PS has no influence on the morphology of the micelles and on the characteristic size of both the PS core and the P2VP shell, although the hydrodynamic diameter of the micelles is decreased. Substitution of styrene for homopolystyrene results in transition from a spherical to a dominant rod-like morphology. © 2004 Published by Elsevier Ltd.

The cycloaddition of diazoazoles with acylisothiocyanates has been found to result in the formation of a 1,2,3,5-thiatriazine ring. This new reaction was used to prepare novel 8-substituted 4-[benzoylimino-4H-imidazo(pyrazolo)][5,1-d] -[1,2,3,5]thiatriazines. The structures of the compounds prepared were carefully studied by X-ray diffraction, IR and NMR spectroscopy.

金沢大学大学院自然科学研究科生理活性物質科学, 金沢大学薬学部, A novel nucleophilic substitution reaction at the 1-position of indole nucleus was discovered by reacting 1-hydroxytryptamine and -tryptophan derivatives with indoles in 85% formic acid yielding 1-(indol-3-yl)indoles. Their structures were determined by X-Ray crystallographic analysis and chemical correlations. An SN2 mechanism on the indole nitrogen (1-position) is proposed.

Encapsulation complexes are reversibly formed assemblies in which small molecule guests are completely surrounded by large molecule hosts. The assemblies are held together by weak intermolecular forces and are dynamic: they form and dissipate on time scales ranging from milliseconds to days—long enough for many interactions, even reactions, to take place within them. Little information is available on the exchange process, how guests get in and out of these complexes. Here we report that these events can be slow enough for conventional kinetic studies, and reactive intermediates can be detected. Guest exchange has much in common with familiar chemical substitution reactions, but differs in some respects: no covalent bonds are made or broken, the substrate is an assembly rather than a single molecule, and at least four molecules are involved in multiple rate-determining steps.

The salts of the monosubstituted hexanuclear anions [Ir6(CO)14X]- [X = Cl (1,)Br (2), I (3), or SCN (4)] have been prepared by treating [Ir6(CO)16] with halides or pseudohalides at room temperature in tetrahydrofuran solution. The three anions consist of slightly distorted octahedra of iridium atoms bearing twelve terminal and two edge bridging carbon monoxide groups. In all cases the halogen atoms or the pseudohalogen group adopt a bridging co-ordination on an Ir-lr edge.

The salts of the monosubstituted hexanuclear anions [Ir6(CO)14X]- [X = Cl (1,)Br (2), I (3), or SCN (4)] have been prepared by treating [Ir6(CO)16] with halides or pseudohalides at room temperature in tetrahydrofuran solution. The three anions consist of slightly distorted octahedra of iridium atoms bearing twelve terminal and two edge bridging carbon monoxide groups. In all cases the halogen atoms or the pseudohalogen group adopt a bridging co-ordination on an Ir-lr edge.

We report a mild Lewis acid induced isomerization of donor-acceptor cyclopropanes, containing an alkenyl moiety and diverse electron-withdrawing group(s) at the adjacent positions, into substituted cyclopentenes. We have found that 1,1,2-trisubstituted cyclopent-3-enes were exclusively obtained in yield of 51-99% when cyclopropanes with a 2-substituted alkenyl group as a donor underwent isomerization. For cyclopropanes bearing a trisubstituted alkenyl group either the corresponding cyclopent-3-enes or isomeric cyclopent-2-enes having two acceptor groups at the C(1) atom were formed, with the reaction selectivity being determined by the applied Lewis acid. We have shown that the reactivity of the donor-acceptor cyclopropane increases with the increase of the electron-donating character of (hetero)aromatic group attached to the alkenyl moiety. The synthetic utility of the developed methodology was also demonstrated through the synthesis of polysubstituted cyclopentane and piperidine derivatives. © 2017 American Chemical Society.

Heating 1-vinyl-4,5,6,7-tetrahydro-5-methyl-4,6-ethanopyrrolo[3,2-c]pyridme (1) in the presence of acetic or trifluoroacetic anhydride resulted in bicyclic saturated fragment cleavage, affording cyclohepteno[b]pyrroles 2a,b in low yields. In the case of trifluoroacetic anhydride, the major product of the reaction, -trifluoroacetylsubstituted tetrahydropyrrolo[3,2-c]pyridine 3 was isolated in 34% yield.

Acylation of 4-(furyl-2)-4-R-aminobut-1-enes and 4-R-4-furfurylaminobut-1- enes with maleic anhydride, acryloyl chloride or allylhalides provided 3-aza-10-oxatricyclo[5.2.1.01.5]decenes. The tricycles are formed via an initial amide formation followed by a stereoselective exo-IMDAF (Intramolecular Diels-Alder of Furan). In case of competing cycloaddition (for compounds possessing two furan or two dienophilic moieties) the most substituted fivemembered cycle is preferably annulated. Refluxing of 4-R-4- furfurylaminobut-1-enes in acetic anhydride led to exo-3-aza-11-oxatricyclo[6.2. 1.01.6]undecenes with the pseudoequatorial substituent R-4. Treatment of 3-aza-10-oxatricyclo[5.2.1.01.5]decenes with PPA at 90-110 °C promoted cyclic ether opening, aromatization and intramolecular cyclization reactions sequence to give the corresponding tetracyclic compounds - tetrahydroisoindolo[2,1-a]quinolines and tetrahydroisoindolo[2,1-b][2] benzazepines in good yields. Unusual products of ipso-substitution in aromatic ring were obtained on cyclization of N-p-R-substituted 2-allyl-4-oxo-3-aza-10- oxatricyclo[5.2.1.01.5]dec-8-enes.

(Chemical Equation Presented) A three component condensation of 2-aminopyrimidines, isocyanides and 4-hydroxybenzaldehydes was studied. 3-Amino-2-(4-hydroxyphenyl)imidazo[1,2-a]pyrimidine derivatives were obtained in moderate yields. Using 4-hydroxy-3,5-dimethoxybenzaldehyde and 2-aminopyrimidine as starting materials in the condensation led to mixtures of isomeric 2- and 3-aminoimidazo[1,2-a]pyrimidines. It was demonstrated, that the regiospecificity of this reaction is mainly defined by the steric hindrance of substituents on the pyrimidine nucleus and the carbonyl activity of the corresponding aldehydes.

Reaction of 5-bromo-2-methyl-8-nitro-1,2,3,4-tetrahydroisoquinoline with activated alkynes affords stable tetrahydropyrrolo[2,1-a]isoquinolin-4-ium ylides. Further reactions of ylide 2 gives access to substituted dihydropyrrolo[2,1-a]isoquinolines in good yields. © 2009 Elsevier Ltd. All rights reserved.