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1.
J Org Chem ; 84(1): 128-139, 2019 Jan 04.
Article in English | MEDLINE | ID: mdl-30511856

ABSTRACT

In addition to phosphanes, olefins, amines, and amides, over the past two decades N-heterocyclic carbene (NHC) has emerged as a useful alternative ligand. Based on a number of derivatization studies on NHC ligands, imidazol-2-ylidene and imidazolin-2-ylidene became the standard heterocyclic form, and bulky substituents have commonly been introduced on the nitrogen(s) adjacent to carbenic carbons. Our group previously developed NHCs equipped with noncarbenic carbons with a bicyclic architecture that gives them unique steric properties that make them bulky but accessible. In this study, we synthesized a novel type of NHC ligand that possesses a bicyclo[2.2.1]heptane architecture, and we compared five derivatives using copper-catalyzed allylic arylations with aryl Grignard reagents. The regioselectivity of the substitution obviously indicates that a phenyl ring over an active site has a characteristic effect on the resultant copper catalysts when γ-substitution is the major pathway.

2.
Chem Pharm Bull (Tokyo) ; 65(4): 396-402, 2017 Apr 01.
Article in English | MEDLINE | ID: mdl-28163272

ABSTRACT

A novel type of molecularly imprinted polymer (MIP), N-benzoyl-(S)-valine anilide-imprinted polymer (IP-2), was prepared using hydrogen-bonding interactions as a main force in the pre-polymerization step. The performance of the IP-2 was evaluated via batch procedure and compared with a (S)-valine anilide-imprinted polymer (IP-1) that was prepared using an ionic interaction that is stronger than hydrogen bonding. Although both polymers showed a preferential adsorbability for (S)-amino acid derivatives, different performances were observed in terms of adsorbability and enantioselectivity. In addition, the IP-2 was able to recognize the enantiomer of a valine-derived chiral catalyst. This phenomenon was applied to a chiral amplification reaction, and a highly selective asymmetric Mannich-type amination was achieved using the combination of a racemic catalyst and a MIP.


Subject(s)
Molecular Imprinting , Polymers/chemistry , Polymers/chemical synthesis , Hydrogen Bonding , Molecular Structure , Polymerization , Stereoisomerism
3.
Org Biomol Chem ; 15(14): 2892-2896, 2017 Apr 05.
Article in English | MEDLINE | ID: mdl-28134374

ABSTRACT

The combination of a "rigid" chiral bicyclic cis-1,2-diamine skeleton with steric bulkiness and a "flexible" achiral linker was newly designed as a bifunctional organocatalyst framework and it showed excellent catalytic activity of up to 0.05 mol%, accompanied by the reversal of enantioselection depending on the position of the linker, in an amine-thiourea organocatalyzed asymmetric Michael reaction.

4.
J Org Chem ; 82(2): 1266-1272, 2017 01 20.
Article in English | MEDLINE | ID: mdl-28029049

ABSTRACT

A nickel half-sandwich complex supported by our original NHC ligand was developed as a robust precatalyst for Suzuki-Miyaura cross-coupling. The addition of PPh3 was a crucial element in the suppression of side reactions and in accelerating the cross-coupling reaction. By employing the optimal conditions, aryl-aryl, heteroaryl-aryl, and heteroaryl-heteroaryl couplings were achieved.

5.
J Org Chem ; 80(19): 9671-81, 2015 Oct 02.
Article in English | MEDLINE | ID: mdl-26349507

ABSTRACT

Imidazol-2-ylidene and imidazolin-2-ylidene are frequently employed as the core structures of N-heterocyclic carbene (NHC) ligands, because these have two nitrogen sites adjacent to carbenic carbons. The electronic and steric effects of N-substituents to a bound metal have been aptly studied, and bulky substituents have commonly been introduced on nitrogen(s). However, too much bulkiness can sometimes result in an ineffectiveness of the hindered substrates. In this study, we thoroughly compared our original bicyclic NHC, which has bulky substituents on its noncarbenic carbons, with ubiquitous NHC ligands to probe its steric properties. A well-defined bicyclic NHC-CuCl complex was successfully synthesized and applied to the copper-catalyzed borylations of aryl halides at ambient temperature. A bicyclic NHC-CuCl proved to be a better catalyst than commonly used NHC ligand-Cu complexes, particularly for sterically hindered substrates, which suggested that the bicyclic NHC ligand offered a bulky but accessible environment to the bound copper.

6.
J Recept Signal Transduct Res ; 34(4): 299-306, 2014 Aug.
Article in English | MEDLINE | ID: mdl-24593255

ABSTRACT

CONTEXT: There are few short-term mouse models of chronic obstructive pulmonary disease (COPD) mimicking the human disease. In addition, p38 is recently recognized as a target for the treatment of COPD. However, the precise mechanism how p38 contributes to the pathogenesis of COPD is still unknown. OBJECTIVE: We attempted to create a new mouse model for COPD by intra-tracheal administration of a mixture of lipopolysaccharide (LPS) and cigarette smoke solution (CSS), and investigated the importance of the p38 mitogen-activated protein kinase (p38) pathway in the pathogenesis of COPD. METHODS: Mice were administered LPS + CSS once a day on days 0-4 and 7-11. Thereafter, CSS alone was administered to mice once a day on days 14-18. On day 28, histopathological changes of the lung were evaluated, and bronchoalveolar lavage fluid (BALF) was subjected to western blot array for cytokines. Transgenic (TG) mice expressing a constitutive-active form of MKK6, a p38-specific activator in the lung, were subjected to our experimental protocol of COPD model. RESULTS: LPS + CSS administration induced enlargement of alveolar air spaces and destruction of lung parenchyma. BALF analyses of the LPS + CSS group revealed an increase in expression levels of several cytokines involved in the pathogenesis of human COPD. These results suggest that our experimental protocol can induce COPD in mice. Likewise, histopathological findings of the lung and induction of cytokines in BALF from MKK6 c.a.-TG mice were more marked than those in WT mice. CONCLUSION: In a new experimental COPD mouse model, p38 accelerates the development of emphysema.


Subject(s)
Emphysema/genetics , MAP Kinase Kinase 6/metabolism , Pulmonary Disease, Chronic Obstructive/genetics , p38 Mitogen-Activated Protein Kinases/genetics , Animals , Disease Models, Animal , Emphysema/etiology , Emphysema/pathology , Humans , Lipopolysaccharides/toxicity , MAP Kinase Kinase 6/genetics , Mice , Mice, Transgenic , Pulmonary Disease, Chronic Obstructive/chemically induced , Pulmonary Disease, Chronic Obstructive/complications , Pulmonary Disease, Chronic Obstructive/pathology , Smoking/adverse effects , Tobacco Products/toxicity , p38 Mitogen-Activated Protein Kinases/biosynthesis
7.
Chem Pharm Bull (Tokyo) ; 61(5): 546-50, 2013.
Article in English | MEDLINE | ID: mdl-23649197

ABSTRACT

We evaluated the adsorbability and selectivity of (S)-valine anilide imprinted molecularly imprinted polymer (MIP) using a batch procedure that is both independent and precise. This study revealed important information about the relationship between the performance of MIPs and experimental factors such as the components of MIP synthesis and a reaction solvent. Herein, we also describe the problems associated with the preparation of a "non-imprinted polymer," which is often used to evaluate the effect of a template molecule, and we propose a new type of reference polymer, "blank polymer."


Subject(s)
Molecular Imprinting , Polymers/chemistry , Valine/chemistry , Adsorption , Molecular Structure , Polymers/chemical synthesis , Surface Properties , Valine/analogs & derivatives
8.
J Biol Chem ; 287(29): 24228-38, 2012 Jul 13.
Article in English | MEDLINE | ID: mdl-22637476

ABSTRACT

One of the mitogen-activated protein kinases, p38, has been found to play a crucial role in various inflammatory responses. In this study, we analyzed the roles of p38α in multiple sclerosis, using an animal model, experimental autoimmune encephalomyelitis (EAE). p38α(+/-) mice (p38α(-/-) showed embryonic lethality) showed less severe neurological signs than WT mice. Adoptive transfer of lymph node cells (LNC) from sensitized WT mice with MOG(35-55) to naive WT-induced EAE was much more severe compared with the case using LNC from sensitized p38α(+/-) mice. Comprehensive analysis of cytokines from MOG(35-55)-challenged LNC by Western blot array revealed that production of IL-17 was significantly reduced by a single copy disruption of the p38α gene or a p38 inhibitor. Likewise, by a luciferase reporter assay, an electrophoresis mobility shift assay, and characterization of the relationship between p38 activity and IL-17 mRNA expression, we confirmed that p38 positively regulates transcription of the Il17 gene. Furthermore, oral administration of a highly specific p38α inhibitor (UR-5269) to WT mice at the onset of EAE markedly suppressed the progression of EAE compared with a vehicle group. These results suggest that p38α participates in the pathogenesis of EAE through IL-17 induction.


Subject(s)
Encephalomyelitis, Autoimmune, Experimental/metabolism , Mitogen-Activated Protein Kinase 14/metabolism , Animals , Electrophoretic Mobility Shift Assay , Encephalomyelitis, Autoimmune, Experimental/drug therapy , Encephalomyelitis, Autoimmune, Experimental/genetics , Enzyme Inhibitors/therapeutic use , Female , Interleukin-17/genetics , Interleukin-17/metabolism , Male , Mice , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Mitogen-Activated Protein Kinase 14/genetics , Promoter Regions, Genetic , RNA Stability/genetics
9.
Life Sci ; 90(17-18): 657-65, 2012 May 15.
Article in English | MEDLINE | ID: mdl-22483694

ABSTRACT

AIMS: CD69 is an early activation marker in lymphocytes and an important signal transmitter in inflammatory processes. However, its role in acute lung injury (ALI) is still unknown. We used a lipopolysaccharide (LPS)-induced mouse model of ALI to study the role of macrophage-surface CD69 in this condition. MAIN METHODS: We investigated bronchoalveolar lavage fluid (BALF) cell subpopulations, myeloperoxidase levels in lung homogenates, lung pathology, and lung oedema in CD69-deficient (CD69(-/-)) mice 24h after LPS instillation. We also determined cytokine/chemokine expression levels in BALF and macrophage culture supernatant from CD69(-/-) and wild type (WT) mice. Also, we investigated CD69, keratinocyte-derived chemokine (KC) and macrophage inflammatory protein (MIP)-2 localization in the lungs after LPS administration. Furthermore, we examined the effect of anti-CD69 antibody on LPS-induced cytokine/chemokine release from cultured macrophages. KEY FINDINGS: Our study shows that intratracheal instillation of LPS-induced neutrophilic infiltration, histopathological changes, myeloperoxidase positivity, and oedema in the lung to a lower degree in CD69(-/-) mice than in WT mice. The immunoreactivities for CD69, KC and MIP2 were induced in the lung of WT mice instilled with LPS and were predominantly localized to the macrophages. Moreover, the cytokine/chemokine expression profile between the two genotypes of cultured macrophages in response to LPS was similar to that observed in the BALF. In addition, anti-CD69 antibody inhibited the LPS-induced cytokine/chemokine expression. SIGNIFICANCE: These results suggest that CD69 on macrophages plays a crucial role in the progression of LPS-induced ALI and may be a potentially useful target in the therapy for ALI.


Subject(s)
Acute Lung Injury/immunology , Antigens, CD/immunology , Antigens, Differentiation, T-Lymphocyte/immunology , Lectins, C-Type/immunology , Lipopolysaccharides/immunology , Lung/immunology , Macrophages/immunology , Acute Lung Injury/genetics , Acute Lung Injury/pathology , Animals , Antigens, CD/analysis , Antigens, CD/genetics , Antigens, Differentiation, T-Lymphocyte/analysis , Antigens, Differentiation, T-Lymphocyte/genetics , Bronchoalveolar Lavage Fluid/cytology , Bronchoalveolar Lavage Fluid/immunology , Cells, Cultured , Chemokine CXCL2/analysis , Chemokine CXCL2/immunology , Chemokines/immunology , Gene Deletion , Lectins, C-Type/analysis , Lectins, C-Type/genetics , Lung/metabolism , Lung/pathology , Male , Mice , Mice, Inbred BALB C , Neutrophils/immunology , Peroxidase/immunology , Peroxidase/metabolism
10.
Respir Res ; 12: 131, 2011 Oct 05.
Article in English | MEDLINE | ID: mdl-21970554

ABSTRACT

BACKGROUND: Cluster of differentiation 69 (CD69), an early activation marker antigen on T and B cells, is also expressed on activated macrophages and neutrophils, suggesting that CD69 may play a role in inflammatory diseases. To determine the effect of CD69 deficiency on bleomycin(BLM)-induced lung injury, we evaluated the inflammatory response following intratracheal BLM administration and the subsequent fibrotic changes in wild type (WT) and CD69-deficient (CD69-/-) mice. METHODS: The mice received a single dose of 3 mg/kg body weight of BLM and were sacrificed at 7 or 14 days post-instillation (dpi). Lung inflammation in the acute phase (7 dpi) was investigated by differential cell counts and cytokine array analyses of bronchoalveolar lavage fluid. In addition, lung fibrotic changes were evaluated at 14 dpi by histopathology and collagen assays. We also used reverse transcription polymerase chain reaction to measure the mRNA expression level of transforming growth factor ß1 (TGF-ß1) in the lungs of BLM-treated mice. RESULTS: CD69-/- mice exhibited less lung damage than WT mice, as shown by reductions in the following indices: (1) loss of body weight, (2) wet/dry ratio of lung, (3) cytokine levels in BALF, (4) histological evidence of lung injury, (5) lung collagen deposition, and (6) TGF-ß1 mRNA expression in the lung. CONCLUSION: The present study clearly demonstrates that CD69 plays an important role in the progression of lung injury induced by BLM.


Subject(s)
Antibiotics, Antineoplastic/toxicity , Bleomycin/toxicity , Lectins, C-Type/deficiency , Pneumonia/pathology , Pulmonary Fibrosis/pathology , Trachea , Animals , Antibiotics, Antineoplastic/administration & dosage , Antigens, CD/genetics , Antigens, Differentiation, T-Lymphocyte/genetics , Bleomycin/administration & dosage , Disease Progression , Lectins, C-Type/genetics , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Pneumonia/chemically induced , Pneumonia/genetics , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/genetics , Trachea/drug effects
11.
Chem Pharm Bull (Tokyo) ; 59(6): 799-801, 2011.
Article in English | MEDLINE | ID: mdl-21628924

ABSTRACT

A simple and inexpensive system comprised of H(2)O(2)-pyridine-FeCl(3)·6H(2)O for the catalysis of olefin epoxidation was established. Intriguingly, the reactivity of this system greatly depends on the amounts of pyridine. Various substrates, including aromatic and aliphatic olefins, were epoxidized by this simple system in moderate to excellent yields.


Subject(s)
Chlorides/chemistry , Epoxy Compounds/chemistry , Ferric Compounds/chemistry , Hydrogen Peroxide/chemistry , Pyridines/chemistry , Alkenes/chemistry , Catalysis
12.
Chem Pharm Bull (Tokyo) ; 58(10): 1419-21, 2010 Oct.
Article in English | MEDLINE | ID: mdl-20930416

ABSTRACT

The preparation of a new class of "roofed" ß-iminodisulfides from sterically congested, conformationally rigid chiral 2-thiazolidinones is described. A functional survey of palladium-catalyzed asymmetric allylic alkylation of 1,3-diphenyl-2-propenyl acetate with dimethyl malonate proved that symmetrical "roofed" ß-iminodisulfides are efficient chiral ligands, showing enantioselectivity opposite that associated with chiral "roofed" ß-iminothioether ligands.


Subject(s)
Disulfides/chemistry , Palladium/chemistry , Alkylation , Catalysis , Ligands , Stereoisomerism
13.
Chem Pharm Bull (Tokyo) ; 50(3): 435-8, 2002 Mar.
Article in English | MEDLINE | ID: mdl-11911217

ABSTRACT

The intramolecular ruthenium(II)-catalyzed radical addition of the trichloroacetyl pendant group to the 2-oxazolone skeleton is greatly enhanced in the presence of catalytic Lewis acids including rare earth metal triflates, thus providing a convenient route to a highly potential chiral synthon for vic-amino alcohols.


Subject(s)
Acids/chemistry , Ruthenium/chemistry , Catalysis , Magnetic Resonance Spectroscopy , Spectrometry, Mass, Fast Atom Bombardment
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