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1.
Chem Pharm Bull (Tokyo) ; 70(3): 240-243, 2022.
Article in English | MEDLINE | ID: mdl-35228389

ABSTRACT

We previously isolated an aminobutadiene derivative as a by-product in the synthesis of a 1,4-dihydropyridine (1,4-DHP) derivative by the reaction of methyl propiolate with excess ammonium acetate in water, and we proposed that it is an intermediate in the formation of 1,4-DHP. Here, to test this idea and to investigate the reaction mechanism, we selectively synthesized the aminobutadiene derivative in EtOH and examined its reactivity. The yield of the aminobutadiene derivative was increased in the presence of excess ammonium salt. X-Ray crystal structure analysis indicated the presence of an intramolecular hydrogen bond between the terminal amine and ester carbonyl oxygen, together with a short C-N bond length consistent with enamine-imine equilibrium. Direct cyclization of the aminobutadiene derivative with methyl propiolate to afford the 1,4-DHP derivative did not proceed well, but the yield was increased in the presence of morpholine salt as an additive. These results suggest that the predominant reaction pathway from the intermediate to 1,4-DHP in water involves Michael addition of a second amine molecule and reaction with methyl propiolate, followed by intramolecular cyclization and elimination of amine.


Subject(s)
Dihydropyridines , Water , Amines/chemistry , Cyclization
2.
ChemSusChem ; 8(21): 3587-9, 2015 Nov.
Article in English | MEDLINE | ID: mdl-26423212

ABSTRACT

The utility and applicability of polyethylene-g-polyacrylic acid-immobilized dimethylaminopyridine (g-DMAP) as a catalyst in a continuous-flow system were investigated for decarboxylative esterification. High catalytic activity toward acylation was provided by g-DMAP containing a flexible grafted-polymer structure. During decarboxylation, carboxylic acids and alcohols were converted cleanly using di-tert-butyl dicarbonate (Boc2O) as a coupling reagent, which reduced by-products. In addition, the use of Boc2O resulted in the formation of tert-butyl esters. These esterifications dramatically reduced the reaction time under continuous-flow conditions, with a residence time of approximately 2 min. This highly efficient esterification procedure will provide more practical industrial applications.


Subject(s)
Acrylic Resins/chemistry , Carbonates/chemistry , Polyethylenes/chemistry , Pyridines/chemistry , Acylation , Alcohols/chemistry , Carboxylic Acids/chemistry , Catalysis , Decarboxylation , Esterification , Molecular Structure
4.
ChemSusChem ; 8(10): 1711-5, 2015 May 22.
Article in English | MEDLINE | ID: mdl-25855359

ABSTRACT

A new heterogeneous organocatalyst, graft polymer supported dimethylaminopyridine (g-DMAP), is developed. This catalyst has a flexible structure and comprises DMAP anchored to the polyethylene-graft-polyacrylic acid (PE-g-PAA). It exhibits higher activity than DMAP supported on polystyrene cross-linked with divinylbenzene and can be recovered in batch mode acetylation. The activity and stability of this catalyst allow its application in continuous flow systems. Continuous acetylation proceeds with excellent conversion, and a turnover number of 560 can be achieved using g-DMAP. Parallel fixed bed reactors were used to scale up the synthesis of this continuous flow system. Eight parallel fixed bed reactors displayed excellent conversion.


Subject(s)
Acrylic Resins/chemistry , Aminopyridines/chemistry , Polyethylenes/chemistry , Catalysis
5.
J Biosci Bioeng ; 102(4): 365-8, 2006 Oct.
Article in English | MEDLINE | ID: mdl-17116586

ABSTRACT

An inhibitor of the prophenoloxidase activation using extract from a silkworm pupa was isolated from a culture filtrate of Cordyceps militaris and identified as dipicolinic acid (DPA). The production of DPA in Clavicipitaceae fungi was examined. Entomogenous fungi that produce DPA were integrated into one group by a phylogenetic analysis based on 18S rDNA. It is suggested that the group acquired an ability to produce DPA during its evolution from plant pathogenic fungi to entomogenous fungi.


Subject(s)
Cordyceps/classification , Cordyceps/metabolism , Picolinic Acids/metabolism , Animals , Cordyceps/genetics , Insecta/microbiology , Species Specificity
6.
J Biosci Bioeng ; 100(6): 631-6, 2005 Dec.
Article in English | MEDLINE | ID: mdl-16473772

ABSTRACT

A trypsin-like protease, P-1-1, was purified from the culture supernatant of the fungus Cordyceps militaris by (NH(4))(2)SO(4) precipitation, chromatography on DEAE Bio-Gel Agarose, TSKgel CM-5PW, and gel-filtration with HiLoad 26/60 Superdex 75 pg, and its properties were examined. Purified P-1-1 showed a single band by SDS-PAGE and was estimated to have a molecular mass of 23,405 by matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS). The optimum pH of the enzyme was between 8.5 and 12.0. It was inhibited strongly by leupeptin and diisopropyl fluorophosphate (DFP), and definitely did by N(alpha)-tosyl-L-lysine chloromethyl ketone hydrochloride (TLCK), phenylmethanesulfonyl fluoride (PMSF) and chymostatin. The carbonyl group sides of Arg and Lys were confirmed as the sites of cleavage by the enzyme toward cecropin B. These results indicate that P-1-1 is a trypsin-type serine protease. The N-terminal amino acid sequence of P-1-1 showed a high homology with those of trypsins or chymotrypsin derived from Diptera insects.


Subject(s)
Cordyceps/enzymology , Diptera/microbiology , Trypsin/biosynthesis , Trypsin/chemistry , Amino Acid Sequence , Animals , Enzyme Activation , Extracellular Fluid/enzymology , Molecular Sequence Data , Peptide Hydrolases/biosynthesis , Peptide Hydrolases/chemistry , Peptide Hydrolases/isolation & purification , Sequence Homology, Amino Acid , Substrate Specificity , Trypsin/isolation & purification
7.
Bioorg Med Chem ; 12(3): 563-70, 2004 Feb 01.
Article in English | MEDLINE | ID: mdl-14738965

ABSTRACT

Despite the enormous health risks, people continue to smoke and use tobacco primarily as a result of nicotine addiction. As part of our immunopharmacotherapy research, the effects of active and passive immunizations on acute nicotine-induced locomotor activity in rats were investigated. To this end, rats were immunized with either a NIC-KLH immunoconjugate vaccine designed to elicit an antinicotine immune response, or were administered an antinicotine monoclonal antibody, NIC9D9, prior to a series of nicotine challenges and testing sessions. Vaccinated rats showed a 45% decrease in locomotor activity compared to a 16% decrease in controls. Passive immunization with NIC9D9 resulted in a 66.9% decrease in locomotor activity versus a 3.4% decrease in controls. Consistent with the behavioral data, much less nicotine was found in the brains of immunized rats. The results support the potential clinical value of immunopharmacotherapy for nicotine addiction in the context of tobacco cessation programs.


Subject(s)
Immunization , Motor Activity , Nicotine/antagonists & inhibitors , Nicotine/immunology , Animals , Brain/metabolism , Hemocyanins/chemistry , Male , Molecular Structure , Motor Activity/drug effects , Nicotine/analysis , Nicotine/pharmacology , Rats , Rats, Wistar
8.
Biosci Biotechnol Biochem ; 67(11): 2402-7, 2003 Nov.
Article in English | MEDLINE | ID: mdl-14646200

ABSTRACT

The chitin-binding domain of human macrophage chitinase was expressed as a fusion protein with glutathione S-transferase in Escherichia coli and assayed for its binding activity. The purified recombinant chitin-binding domain bound to chitin, but not to glucan, xylan, or mannan. The binding of the recombinant chitin-binding domain to chitin was inhibited by N-acetylglucosamine, di-N-acetylchitobiose, and hyaluronan, but not by N-acetylgalactosamine or chondroitin. Furthermore, a solid-phase binding assay showed that the recombinant domain interacts specifically with hyaluronan and hybrid-type N-linked oligosaccharide chains on glycoproteins, and that the oligosaccharide-binding characteristics are similar to those of wheat germ agglutinin, a lectin that binds to chitin. The results suggest that human chitinase chitin-binding domain may be involved in tissue remodeling through binding to polysaccharides or extracellular matrix glycoproteins, and this recombinant protein can be used to elucidate biological functions of the enzyme.


Subject(s)
Chitin/metabolism , Chitinases/metabolism , Macrophages/enzymology , Base Sequence , Binding Sites , Chitinases/isolation & purification , Cloning, Molecular , DNA Primers , Escherichia coli/enzymology , Escherichia coli/genetics , Glutathione Transferase/isolation & purification , Glutathione Transferase/metabolism , Humans , Oligosaccharides/metabolism , Polymerase Chain Reaction , Recombinant Fusion Proteins/isolation & purification , Recombinant Fusion Proteins/metabolism , Substrate Specificity
9.
J Am Chem Soc ; 124(14): 3661-8, 2002 Apr 10.
Article in English | MEDLINE | ID: mdl-11929256

ABSTRACT

One aspect of immunopharmacotherapy for cocaine abuse involves the use of a catalytic monoclonal antibody (mAb) to degrade cocaine via hydrolysis of the benzoate ester. A cocaine benzoylthio ester analogue provides a means to implement high-throughput selection strategies to potentially isolate mAbs with high activity. The required analogue was synthesized starting from (-)-cocaine hydrochloride and possessed the cocaine absolute configuration. Key points in the preparation were the introduction of the sulfur atom at C-3 via a bromomagnesium thiolate addition to the exo face of anhydroecgonine, separation of C-2 diastereomers, recycling of a C-2 thio ester byproduct, and formation of the necessary C-2 methyl and C-3 benzoylthio esters. Effects resulting from the lower electronegativity and greater hydrophobicity of sulfur compared to oxygen were observed. These characteristics could result in interesting drug properties. Furthermore, the analogue was found to be a substrate for catalytic mAbs that hydrolyze cocaine as monitored by HPLC and also spectrophotometry by coupling cleavage of the benzoylthio ester to the disulfide exchange with Ellman's reagent. Screening antibody libraries with the new cocaine analogue using the spectroscopic assay provides an avenue for the high-throughput identification of catalysts that efficiently breakdown cocaine.


Subject(s)
Cocaine/analogs & derivatives , Cocaine/chemical synthesis , Antibodies, Catalytic/chemistry , Antibodies, Catalytic/metabolism , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/metabolism , Cocaine/chemistry , Cocaine/metabolism , Cocaine-Related Disorders/therapy , Humans , Molecular Conformation
10.
Bioorg Med Chem Lett ; 12(6): 861-4, 2002 Mar 25.
Article in English | MEDLINE | ID: mdl-11958980

ABSTRACT

Vancomycin resistance is currently a major healthcare problem. The development of a catalytic monoclonal antibody (mAb) that hydrolyzes the D-Ala-D-Lac depsipeptide provides a potentially novel antibiotic strategy. A phosphonate hapten design was used to program antibody catalysis. The characteristics of the hapten were shown to be important for obtaining a viable immune response and several catalytic mAbs that cleave a peptidoglycan model substrate. The best mAb afforded a >500-fold rate enhancement over background.


Subject(s)
Antibodies, Monoclonal/metabolism , Dipeptides/chemistry , Animals , Antibodies, Monoclonal/therapeutic use , Catalysis , Dipeptides/immunology , Drug Resistance , Haptens/chemistry , Haptens/immunology , Hydrolysis , Kinetics , Mice , Organophosphonates , Vancomycin
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