- Irreversible inhibitors of the proline racemase unveil innovative mechanism of action as antibacterial agents against Clostridioides difficile
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Proline racemases (PRAC), catalyzing the l-proline and d-proline interconversion, are essential factors in eukaryotic pathogens such as Trypanosoma cruzi, Trypanosoma vivax, and Clostridioides difficile. If the discovery of irreversible inhibitors of T.?cruzi PRAC (TcPRAC) led to innovative therapy of the Chagas disease, no inhibitors of CdPRAC have been discovered to date. However, C.?difficile, due to an increased incidence in recent years, is considered as a major cause of health threat. In this work, we have taken into account the similarity between TcPRAC and CdPRAC enzymes to design new inhibitors of CdPRAC. Starting from (E) 4-oxopent-2-enoic acid TcPRAC irreversible inhibitors, we synthesized 4-aryl substituted analogs and evaluated their CdPRAC enzymatic inhibition against eleven strains of C.?difficile. This study resulted in promising candidates and allowed for identification of (E)-4-(3-bromothiophen-2-yl)-4-oxobut-2-enoic acid 20 that was chosen for complementary in vivo studies and did not reveal in vivo toxicity.
- Barbut, Frédéric,Blondel, Arnaud,Gateau, Cécile,Gouault, Nicolas,Melo, Guilherme D.,Minoprio, Paola,Renault, Jacques,Tasseau, Olivier,Uriac, Philippe
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- Integrating Biomass into the Organonitrogen Chemical Supply Chain: Production of Pyrrole and d-Proline from Furfural
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Production of renewable, high-value N-containing chemicals from lignocellulose will expand product diversity and increase the economic competitiveness of the biorefinery. Herein, we report a single-step conversion of furfural to pyrrole in 75 % yield as a key N-containing building block, achieved via tandem decarbonylation–amination reactions over tailor-designed Pd?S-1 and H-beta zeolite catalytic system. Pyrrole was further transformed into dl-proline in two steps following carboxylation with CO2 and hydrogenation over Rh/C catalyst. After treating with Escherichia coli, valuable d-proline was obtained in theoretically maximum yield (50 %) bearing 99 % ee. The report here establishes a route bridging commercial commodity feedstock from biomass with high-value organonitrogen chemicals through pyrrole as a hub molecule.
- Di, Lu,Fung Kin Yuen, Vincent,Song, Song,Sun, Qiming,Yan, Ning,Zhou, Kang
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supporting information
p. 19846 - 19850
(2020/09/02)
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- Cyclic tetrapeptides from the marine strain Streptomyces sp. PNM-161a with activity against rice and yam phytopathogens
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Two cyclotetrapeptides, henceforth named Provipeptides A (1) and B (2), along with five known diketopiperazines (3–7) were isolated from the liquid culture of marine Streptomyces sp. 161a recovered from a sample of sea grass Bryopsis sp. The structures of cyclotetrapeptides and diketopiperazines (DKPs) were established by 1D and 2D NMR data, MS, and by comparison with literature data. The absolute stereochemistry of compounds cyclo-(l-Pro-l-Leu-d-Pro-l-Phe) 1 and cyclo-(-Pro-Ile-Pro-Phe) 2 was established by the Marfey’s method. Compound 1 showed antibacterial activity against rice phytopathogenic strains Burkholderia glumae (MIC = 1.1 mM) and Burkholderia gladioli (MIC = 0.068 mM), compound 2 was active only against B. glumae (MIC = 1.1 mM), and DKP cyclo-[l-Pro-l-Leu] 5 showed to be active against B. gladioli (MIC = 0.3 mM) and B. glumae (MIC = 2.4 mM). Compounds 1 and 2 showed 65% and 50% inhibition of Colletotrichum gloeosporioides (yam pathogen) conidia germination, respectively at a concentration of 1.1 mM.
- Betancur, Luz A.,Forero, Abel M.,Romero-Otero, Adriana,Sepúlveda, Lady Yohanna,Moreno-Sarmiento, Nubia C.,Castellanos, Leonardo,Ramos, Freddy A.
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p. 744 - 751
(2019/07/05)
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- Chemical structure of cichorinotoxin, a cyclic lipodepsipeptide that is produced by Pseudomonas cichorii and causes varnish spots on lettuce
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Pseudomonas cichorii, which causes varnish spots on lettuce and seriously damages lettuce production during the summer season in the highland areas of Japan (e.g., Nagano and Iwate prefectures) was isolated. The structure of a toxin produced by this organism was analyzed based on the detailed evaluation of its 2D NMR and FABMS spectra, and this compound has not been reported previously. We propose the name cichorinotoxin for this toxin. In conjunction with the D or L configurations of each amino acid, which were determined by Marfey’s method, we propose the structure of cichorinotoxin to be as follows: 3-hydroxydecanoyl-(Z)-dhThr1-D-Pro2-D-Ala3-D-Ala4-D-Ala5-D-Val6-D-Ala7-(Z)-dhThr8-Ala9-Val10-D-Ile11-Ser12-Ala13-Val14-Ala15-Val16-(Z)-dhThr17-D-alloThr18-Ala19-L-Dab20-Ser21-Val22, and an ester linkage is present between D-alloThr18 and Val22 (dhThr: 2-aminobut-2-enoic acid; Dab: 2,4-diaminobutanoic acid). Thus, the toxin is a lipodepsipeptide with 22 amino acids. The mono- and tetraacetate derivatives and two alkaline hydrolysates, compounds A and B, were prepared. We discuss here the structure–activity relationships between the derivatives and their necrotic activities toward lettuce.
- Komatsu, Hidekazu,Shirakawa, Takashi,Uchiyama, Takeo,Hoshino, Tsutomu
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p. 299 - 309
(2019/02/20)
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- Method for synthesizing D-proline
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The invention belongs to the technical field of synthesis of chiral organic compounds, and especially relates to a method for synthesizing D-proline. The method comprises the following steps: taking pyrrolidine-2-carbaldehyde, dissolving the pyrrolidine-2-carbaldehyde in an organic solvent, adding a catalyst and an organic alkali potassium t-butoxide, and carrying out an asymmetric catalysis hydrogenation reaction to obtain an intermediate II; and carrying out an oxidation reaction on the intermediate II and an oxidant to obtain the product D-proline III. The method for synthesizing D-prolinehas the following advantages: the use amount of the catalyst is small, and the catalyst can be used repeatedly, so the cost is saved; the solvent used in the synthesis process is a common solvent, sothe method has the characteristics of low cost, non-toxicity, no pollution, greenness and environmental protection; and the synthesis method has a simple process, the yield in the invention is higherthan the yield in the prior art, and the optical purity of the obtained product is high, so the method is suitable for industrial production.
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Paragraph 0026; 0030-0032; 0035
(2018/07/30)
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- Antibacterial low-molecular-weight compounds produced by the marine bacterium Rheinheimera japonica KMM 9513T
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Strain KMM 9513T was isolated from a sediment sample collected from the Sea of Japan seashore and selected due to its ability to inhibit indicator bacterial growth. The strain KMM 9513T has been recently described as a novel species Rheinheimera japonica. This study was undertaken to determine which substances produced by strain KMM 9513T could be responsible for its antimicrobial activity. Eight compounds were obtained from an ethyl acetate extract of R. japonica KMM 9513T. The structures of five diketopiperazines (4–8) and diisobutyl-, dibutyl- and bis(2-ethylhexyl) phthalates (1–3) were established on the basis of detailed interpretation of NMR data, by Marfey method and optical rotation data. The structures of diketopiperazines were determined as cyclo-(l-valyl-l-proline), cyclo-(l-valyl-d-proline), cyclo-(l-phenylalanyl-l-proline), cyclo-(l-leucyl-l-proline), and cyclo-(l-phenylalanyl-d-proline). Compounds 1–3, 5 and 8 revealed antimicrobial activities against Bacillus subtilis and/or Enterococcus faecium and Staphylococcus aureus. In this paper, we describe the isolation and structural elucidation of the isolated compounds 1–8. This is the first report of the characterisation of low molecular weight antibacterial metabolites produced by a member of the genus Rheinheimera.
- Kalinovskaya, Natalia I.,Romanenko, Lyudmila A.,Kalinovsky, Anatoly I.
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p. 719 - 726
(2017/04/14)
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- Chromatographic Resolution of α-Amino Acids by (R)-(3,3'-Halogen Substituted-1,1'-binaphthyl)-20-crown-6 Stationary Phase in HPLC
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Three new chiral stationary phases (CSPs) for high-performance liquid chromatography were prepared from R-(3,3'-halogen substituted-1,1'-binaphthyl)-20-crown-6 (halogen = Cl, Br and I). The experimental results showed that R-(3,3'-dibromo-1,1'-binaphthyl)-20-crown-6 (CSP-1) possesses more prominent enantioselectivity than the two other halogen-substituted crown ether derivatives. All twenty-one α-amino acids have different degrees of separation on R-(3,3'-dibromo-1,1'-binaphthyl)-20-crown-6-based CSP-1 at room temperature. The enantioselectivity of CSP-1 is also better than those of some commercial R-(1,1'-binaphthyl)-20-crown-6 derivatives. Both the separation factors (α) and the resolution (Rs) are better than those of commercial crown ether-based CSPs [CROWNPAK CR(+) from Daicel] under the same conditions for asparagine, threonine, proline, arginine, serine, histidine and valine, which cannot be separated by commercial CR(+). This study proves the commercial usefulness of the R-(3,3'-dibromo-1,1'-binaphthyl)-20-crown-6 chiral stationary phase.
- Wu, Peng,Wu, Yuping,Zhang, Junhui,Lu, Zhenyu,Zhang, Mei,Chen, Xuexian,Yuan, Liming
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supporting information
p. 1037 - 1042
(2017/07/25)
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- (-)/(+)-Sparteine induced chirally-active carbon nanoparticles for enantioselective separation of racemic mixtures
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Chiral carbon nanoparticles (CCNPs) were developed by surface passivation using the chiral ligand (-)-sparteine or (+)-sparteine (denoted (-)-SP/CNP and (+)-SP/CNP, respectively). The chirality of the prepared CCNPs was demonstrated by circular dichroism
- Vulugundam, Gururaja,Misra, Santosh K.,Ostadhossein, Fatemeh,Schwartz-Duval, Aaron S.,Daza, Enrique A.,Pan, Dipanjan
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p. 7513 - 7516
(2016/06/14)
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- An easy 'Filter-and-Separate' method for enantioselective separation and chiral sensing of substrates using a biomimetic homochiral polymer
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We present a polyfluorene appended with protected l-glutamic acid that exhibited a reversible α-helix/β-sheet-like conformation and helical porous fibrous morphology mimicking the super-structure of proteins. The new homochiral polymer probe enabled efficient heterogeneous enantioselective separation and chiral sensing of a wide variety of substrates from their aqueous racemic mixture using an easy 'Filter-and-Separate' method.
- Senthilkumar,Asha
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supporting information
p. 8931 - 8934
(2015/05/27)
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- Asymmetric synthesis of d -proline, d -pipecolic acid, (2 R,3 S,4 R)-3,4-dihydroxyproline, and 1,4-Dideoxy-1,4-imino- d -talitol from a Common Precursor
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Methodology involving stereoselective aza-Michael addition and ring-closing metathesis as key steps has been developed for the preparation of (2R)-pipecolic acid, (2R)-proline, (2R,3S,4R)-3,4-dihydroxyproline, and the known glycosidase inhibiting azasugar 1,4-dideoxy-1,4-imino-d-talitol from a common starting material namely (R)-cyclohexylideneglyceraldehyde in good overall yields. Georg Thieme Verlag Stuttgart New York.
- Chattopadhyay, Shital K.,Mukherjee, Jyoti Prasad
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p. 2481 - 2488
(2014/10/15)
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- Asymmetric Synthesis of d -Proline, d -Pipecolic Acid, (2 R,3 S,4 R)-3,4-Dihydroxyproline, and 1,4-Dideoxy-1,4-imino- d -talitol from a Common Precursor
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Methodology involving stereoselective aza-Michael addition and ring-closing metathesis as key steps has been developed for the preparation of (2R)-pipecolic acid, (2R)-proline, (2R,3S,4R)-3,4-dihydroxyproline, and the known glycosidase inhibiting azasugar 1,4-dideoxy-1,4-imino-d-talitol from a common starting material namely (R)-cyclohexylideneglyceraldehyde in good overall yields.
- Chattopadhyay, Shital K.,Mukherjee, Jyoti Prasad
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p. 2481 - 2488
(2015/12/26)
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- Psychrophilin E, a new cyclotripeptide, from co-fermentation of two marine alga-derived fungi of the genus Aspergillus
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Chemical investigation of the mycelial extract of a mixed culture of two marine alga-derived fungal strains of the genus Aspergillus has yielded one new cyclotripeptide, psychrophilin E (1), the recently reported oxepin-containing alkaloids, protuboxepin A (2) and oxepinamide E (3), together with three other polyketide derivatives (4-6). The chemical structure and relative and absolute configurations of psychrophilin E (1) were unambiguously established based on HRMS, 1D, 2D NMR and chiral-phase HPLC analysis of its hydrolysate. All the isolated compounds were assessed for their anti-proliferative activity against four different human cancer cell lines and some of them revealed selective activities. 2014
- Ebada, Sherif S.,Fischer, Thomas,Hamacher, Alexandra,Du, Feng-Yu,Roth, Yoen Ok,Kassack, Matthias U.,Wang, Bin-Gui,Roth, Eckhard H.
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p. 776 - 781
(2014/06/09)
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- SEPARATING AGENT AND MANUFACTURING METHOD THEREOF
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An embodiment of the present invention is a separating agent wherein a group represented by a chemical formula of: or a group represented by a chemical formula of: is introduced on a surface thereof.
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Paragraph 0067; 0068; 0069; 0070; 0071; 0072; 0075; 0076
(2015/01/07)
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- Cycloforskamide, a cytotoxic macrocyclic peptide from the sea slug Pleurobranchus forskalii
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A macrocylic dodecapeptide, cycloforskamide, was isolated from the sea slug Pleurobranchus forskalii, collected off Ishigaki Island, Japan. Its planar structure was deduced by extensive NMR analyses and was further confirmed by MS/MS fragmentation analyses. Finally, the absolute configuration was determined by total hydrolysis and chiral-phase gas chromatographic analysis. This novel dodecapeptide contains three d-amino acids and three thiazoline heterocycles and exhibits cytotoxicity against murine leukemia P388 cells, with an IC 50 of 5.8 μM.
- Tan, Karen Co,Wakimoto, Toshiyuki,Takada, Kentaro,Ohtsuki, Takashi,Uchiyama, Nahoko,Goda, Yukihiro,Abe, Ikuro
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p. 1388 - 1391
(2013/08/23)
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- Aminolytic reaction catalyzed by d-stereospecific amidohydrolases from Streptomyces spp
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From investigation of 2000 soil isolates, we identified two serine-type amidohydrolases that can hydrolyze d-aminoacyl derivatives from the culture supernatant of Streptomyces species 82F2 and 83D12. The enzymes, redesignated as 82F2-DAP and 83D12-DAP, were purified for homogeneity and characterized. Each enzyme had molecular mass of approximately 40 kDa, and each showed moderate stability with respect to temperature and pH. Among hydrolytic activities toward d-aminoacyl-pNAs, the enzymes showed strict specificity toward d-Phe-pNA, but showed broad specificity toward d-aminoacyl esters. The specific activity for d-Phe-pNA hydrolysis of 82F2-DAP was ten-fold higher than that of 83D12-DAP. As a second function, each enzyme showed peptide bond formation activity by its function of aminolysis reaction. Based on results of d-Phe-d-Phe synthesis under various conditions, we propose a reaction mechanism for d-Phe-d-Phe production. Furthermore, the enzymes exhibited peptide elongation activity, producing oligo homopeptide in a one-pot reaction. We cloned the genes encoding each enzyme, which revealed that the primary structure of each enzyme showed 30-60% identity with those of peptidases belonging to the clan SE, S12 peptidase family categorized as serine peptidase with d-stereospecificity.
- Arima, Jiro,Ito, Hitomi,Hatanaka, Tadashi,Mori, Nobuhiro
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experimental part
p. 1460 - 1469
(2012/01/12)
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- Systematic chemical mutagenesis identifies a potent novel apratoxin A/E hybrid with improved in vivo antitumor activity
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Apratoxins are cytotoxic marine natural products that prevent cotranslational translocation early in the secretory pathway. We showed that apratoxins downregulate receptors and growth factor ligands, giving a one"two punch to cancer cells, particularly those that rely on autocrine loops. Through total synthesis, we tested the effects of amino acid substitutions, including alanine scanning, on the downregulation of receptor tyrosine kinases and vascular endothelial growth factor A (VEGF-A) and probed the stereospecificity of target engagement by epimerization of selected chiral centers. Differential effects on two types of secretory molecules suggest that the apratoxins' substrate selectivity with respect to inhibition of secretion may be tuned through structural modifications to provide tailored therapy. Our structure"activity relationship studies and medicinal chemistry efforts led to a potent inhibitor with in vivo efficacy in a colorectal tumor xenograft model without irreversible toxicity exerted by apratoxin A, demonstrating that this novel mechanism of action has therapeutic potential.
- Chen, Qi-Yin,Liu, Yanxia,Luesch, Hendrik
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supporting information; experimental part
p. 861 - 865
(2012/01/05)
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- Chiral imprinting with amino acids of ordered mesoporous silica exhibiting enantioselectivity after calcination
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Chiral ordered mesoporous silica (COMS) was synthesized in basic media by combining tetraethyl orthosilicate and quaternized aminosilane (with a templating role) silica sources together with four different standard amino acids (arginine, histidine, isoleucine, and proline). Besides the hexagonal MCM-41-type structure, narrow pore size distribution, and high specific surface area, it was found that these solids have potential for enantiomeric separation because of the transference of chirality from the amino acid to the silica. This is illustrated by the resolution of several racemic mixtures (those of proline, isoleucine, trans-4-hydroxyproline, pipecolic acid, valine, leucine, and phenylglycine) with the calcined COMS prepared with l-proline. The opposite behavior observed in induced circular dichroism experiments with calcined COMS, obtained using both enantiomers of proline, confirmed their chiral nature. The high number and variety of existing amino acids, and chiral organic compounds in general, makes these ordered silicas attractive for the production of enantiopure substances.(Figure Presented)
- Lacasta, Susana,Sebastian, Victor,Casado, Clara,Mayoral, Alvaro,Romero, Pilar,Larrea, Angel,Vispe, Eugenio,Lopez-Ram-De-Viu, Pilar,Uriel, Santiago,Coronas, Joaquin
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scheme or table
p. 1280 - 1287
(2012/02/15)
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- Human cancer cell proliferation inhibition by a pentapeptide isolated and characterized from rice bran
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Food-derived bioactive peptides promote functional activity against diseases and present as nutraceutical agents. The purpose of our research was to isolate and fully characterize peptide(s) derived from rice bran having anti-cancer properties. Gastrointestinal juices resistant peptide fractions were initially generated from heat stabilized de-fatted rice bran from which a cell titer assay that uses a tetrazolium dye [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl) -2H-tetrazolium, inner salt; (MTS)] and the electron coupling reagent, phenazine methosulfate. Ion-exchange chromatography elutes that showed anti-cancer properties were further purified to liberate pure peptide. The pure peptide at 600-700 μg/mL dose caused 84% inhibition to colon cancer cells (Caco-2, HCT-116) growth, 80% to breast cancer cells (MCF-7, MDA-MB-231) growth and 84% to liver cancer cells (HepG-2) growth. Mass spectrometry analysis and de novo sequencing revealed the sequence of Glu-Gln-Arg-Pro-Arg for the peptide with a molecular mass of 685.378 Da. A novel pentapeptide was isolated from rice bran to possess cancer growth inhibitory properties on colon, breast, lung and liver cancer cells. This peptide could serve as a nutraceutical agent against cancer.
- Kannan, Arvind,Hettiarachchy, Navam S.,Lay, Jackson O.,Liyanage, Rohana
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experimental part
p. 1629 - 1634
(2010/11/16)
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- Efficient syntheses of enantioenriched (R)-pipecolic acid and (R)-proline via electrophilic organocatalytic amination
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Five-step syntheses of (R)-pipecolic acid and (R)-proline are described, respectively, from cyclohexene and cyclopentene. The key step involves the organocatalytic α-amination of functionalized aldehydes.
- Kalch, Delphine,Rycke, Nicolas De,Moreau, Xavier,Greck, Christine
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body text
p. 492 - 494
(2009/05/07)
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- Resolution of racemic N-benzyl α-amino acids by liquid-liquid extraction: A practical method using a lipophilic chiral cobalt(III) salen complex and mechanistic studies
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The efficient resolution of racemic N-benzyl α-amino acids (N-Bn-AA) has been achieved by a liquid-liquid extraction process using the lipophilic chiral salen-cobalt(III) complex [CoIII(3)(OAc)]. As a result of the resolution by extraction, one enantiomer (S) of the N-benzyl α-amino acid predominated in the aqueous phase, while the other enantiomer (R) was driven into the organic phase by complexation to cobalt. The complexed amino acid (R) was then quantitatively released by a reductive (CoIII→Co II) counter-extraction with aqueous sodium dithionite or L-ascorbic acid in methanol. The reductive cleavage allowed to recover the [Co II(3)] complex in good yield, which could be easily re-oxidized to [CoIII(3)(OAc)] with air/AcOH and reused with essentially no loss of reactivity and selectivity. Investigation on the nitrogen substitution indicates that the presence of a single benzyl group on the amino acid nitrogen is important to obtain high enantioselectivity in the extraction process. The kinetic vs. thermodynamic nature of the resolution process was also investigated with an enantiomeric exchange experiment, which shows that the liquid-liquid extraction with [CoIII(3)-(OAc)] is an equilibrium process operating under thermodynamic control. In the absence of a suitable crystal structure of the [CoIII(3)(N-Bn-AA)] complexes, computational and spectroscopic studies were used to investigate how the N-benzyl α-amino acids are accommodated in the "binding pocket" of the chiral cobalt complex. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.
- Dzygiel, Pawel,Reeve, Toby B.,Piarulli, Umberto,Krupicka, Martin,Tvaroska, Igor,Gennari, Cesare
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supporting information; experimental part
p. 1253 - 1264
(2009/04/07)
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- Kinetic resolution of protected α-amino acid derivatives by a chiral O-nucleophilic acyl transfer catalyst
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The kinetic resolution of α-trifluoroacetamido N-acyl oxazolidinethiones using 5-10% of the chiral, nonracemic O-nucleophilic acyl transfer catalyst 2 is described. A variety of substrates participate in this reaction in excellent yields, with s-factors ranging from 20 to 86. Copyright
- Notte, Gregory T.,Sammakia, Tarek
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p. 4230 - 4231
(2007/10/03)
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- Relationship between the hydrophobicity of dipeptides and the Michaelis-Menten constant Km of their hydrolysis by carboxypeptidase-Y and carboxypeptidase-A
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The enzymatic hydrolysis of dipeptides by carboxypeptidase-Y and carboxypeptidase-A was investigated. In the enzymatic hydrolysis of the dipeptides, a good linear relationship (r = 0.997 and 0.999) was found between the Michaelis-Menten constant (Km) and the hydrophobicity of the substrates evaluated from relative elution volume in reversed-phase HPLC. The correlation suggests that the hydrophobicity of the C-terminal amino acid is a major factor in governing the stability of the enzyme-substrate complex. The difference in the slope of the linear-regression lines seems to reflect the degree of relative hydrophobicity of the binding pockets in carboxypeptidase-Y and carboxypeptidase-A.
- Kanosue, Yoshifumi,Kojima, Satoshi,Hiraga, Yoshikazu,Ohkata, Katsuo
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p. 1187 - 1193
(2007/10/03)
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- Masked oxo sulfinimines (N-sulfinyl imines) in the asymmetric synthesis of proline and pipecolic acid derivatives.
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[structure: see text]. On addition of Et2AlCN/i-PrOH, masked oxo sulfinimines give alpha-amino nitriles that afford oxo alpha-amino acids on hydrolysis. These amino acids cyclize and are reduced to cis proline and cis pipecolic acids derivatives in high ee and good yield. This new procedure avoids many of the limitations related to the preparation of oxo amino acids from proteinogenic amino acids.
- Davis,Zhang,Lee
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p. 759 - 762
(2007/10/03)
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- Compounds for and methods of inhibiting matrix metalloproteinases
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The present invention relates to compounds of Formula I that inhibit matrix metalloproteinases and to a method of inhibiting matrix metalloproteinases using the compounds More particularly, the present invention relates to a method of treating diseases in which matrix metalloproteinases are involved such as multiple sclerosis, atherosclerotic plaque rupture, restenosis, aortic aneurysm, heart failure, periodontal disease, corneal ulceration, burns, decubital ulcers, chronic ulcers or wounds, cancer metastasis, tumor angiogenesis, osteoporosis, rheumatoid or osteoarthritis, renal disease, left ventricular dilatation, or other autoimmune or inflammatory diseases dependent upon tissue invasion by leukocytes.
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- Amino acid conjugates of cyclohexapeptidyl amines
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Novel amino acid conjugates of cyclohexa-peptidyl amines having the formula STR1 and having antifungal and antiparasital properties are described. The compounds exhibit less acute toxicity than the free amines.
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- Enantiospecific syntheses of (R)- and (S)-proline and some derivatives from D-glucono-1,5-lactone
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Carbohydrate-based enantiospecific syntheses of (R)-proline 1 and (S)-proline 2 from the previously reported D-erythro-hexonate ester 9 are described. Azide-substitution reactions on appropriately activated intermediates derived from ester 9, followed by reductive cyclization (H2/Pd-C), gave the substituted pyrrolidines 14 and 22, which were converted into their corresponding N-Cbz derivatives 16 and 24 in conventional manner. Mild acidic hydrolysis of these, followed by oxidation (sodium metaperiodate), gave the protected prolinals 3 and 4, which on further oxidation (sodium chlorite), followed by catalytic hydrogenolysis, gave the prolines 1 and 2. The N-Cbz-prolinol derivatives 5 and 6 are also reported.
- Mazzini, Claudio,Sambri, Letitia,Regeling, Henk,Zwanenburg, Binne,Chittenden, Gordon J. F.
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p. 3351 - 3356
(2007/10/03)
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- BENZYLPYRROLIDINE DERIVATIVES AS DOPAMINE AGONISTS
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Dopamine agonist compounds disclosed are useful in treating hypertension and congestive heart failure in mammals. The compounds have the following general formula (I) STR1 wherein: X is nitrogen or CH; R is hydrogen or lower alkyl;R 1, R' 1, R 2, R' 2, R 3, R' 3, R 4, R' 4, R 5 and R' 5 are each independently hydrogen, STR2 respectively represent--(CH 2) n--and (CH 2) m wherein n and m are each independently an integer of from 1 to 10 and pharmaceutically acceptable salts, S stereoisomers and racemic and non-racemic mixtures thereof.
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- Asymmetric Transformations of Proline and 2-Piperidinecarboxylic Acid via Formation of Salts with Optically Active Tartaric Acid
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The rates of racemization of optically active proline and 2-piperidinecarboxylic acid by using aldehydes as a catalyst tended to increase with a decrease in the acidity of the carboxylic acid used as solvent.Based on these results, the asymmetric transformations of DL-Pro and (RS)-Pia were carried out via formation of salts with (2R,3R)-tartaric acid to give optically pure L-Pro in over 80percent yield and (R)-Pia in 70percent yield.The asymmetric transformation of L-Pro was more successfully achieved by using (2S,3S)-tartaric acid to give optically pure D-Pro in 85percent yield based on the starting L-Pro.
- Shiraiwa, Tadashi,Shinjo, Kazuyuki,Kurokawa, Hidemoto
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p. 3251 - 3255
(2007/10/02)
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- Facile Production of (R)-Proline by Asymmetric Transformation of (S)-Proline
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The asymmetric transformation of (S)-proline ((S)-Pro) through formation of the salt with (2S, 3S)-tartaric acid achieved in the presence of 0.1 molar equivalent of butanal in butanoic acid at 80 deg C to obtain (R)-Pro.The purified salt gave (R)-Pro with 100percent optical purity in 85percent yield.
- Shiraiwa, Tadashi,Shinjo, Kazuyuki,Kurokawa, Hidemoto
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p. 1413 - 1414
(2007/10/02)
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- Method of making a diastereomeric mixture containing two diastereomeric N-acyl-amino acid esters
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In the process of hydrocarboxylating an α-enamide with CO and an organic hydroxyl compound to produce a N-acyl-α-amino acid ester, the improvement comprising using as the organic hydroxyl compound reactant, an organic hydroxyl compound which has a chiral center that is essentially all L or D, thereby producing a reaction mixture having essentially no enantiomeric pairs and containing diastereomeric N-acyl-α-amino acid esters having two chiral centers.
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- Method of making a diastereomeric mixture containing two diastereomeric N-acyl-amino acid esters
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In the process of hydrocarboxylating an α-enamide with CO and an organic hydroxyl compound to produce a N-acyl-α-amino acid ester, the improvement comprising using as the organic hydroxyl compound reactant, an organic hydroxyl compound which has a chiral center that is essentially all L or D, thereby producing a reaction mixture having essentially no enantiomeric pairs and containing diastereomeric N-acyl-α-amino acid esters having two chiral centers.
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- Synthesis of Enantio- and Diastereoiso-merically Pure Substituted Prolines via Condensation of Glycine with Olefins Activated by a Carbonyl Group
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The glycine fragment in the nickel(II) complex (1) formed from the Schiff's base of glycine and (S)-o-benzophenone (2) undergoes base-catalysed Michael addition to acrylaldehyde, α-methylacrylaldehyde, (E)-crotonaldehyde, (E)-cinnamaldehyde, and methyl vinyl ketone.No products of 1,2-addition were found in the Et3N-catalysed reactions.Addition followed by epimerization of the isomeric complexes proceeds with high diastereoselectivity at Cα (90percent) and Cβ of the corresponding amino acid side chains.After chromatographic separation, the diastereoisomerically pure complexes were decomposed and the resulting dihydropyrrole-2-carboxylic acids reduced with NaBH3CN to give (S)-proline, trans-3-methyl-(S)-proline, trans-5-phenyl-(S)-proline, and a mixture of cis- and trans-5-methyl-(S)-prolines.The chiral auxiliary (2) was recovered in 80-90percent yield.
- Belokon', Yuri N.,Bulychev, Aleksandr G.,Pavlov, Viacheslav A.,Fedorova, Eugenia B.,Tsyryapkin, Vladimir A.,et al.
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p. 2075 - 2084
(2007/10/02)
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- RESOLUTION AND USE IN α-AMINO ACID SYNTHESIS OF IMIDAZOLIDINONE GLYCINE DERIVATIVES
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The imidazolidinones (rac.-1 and rac.-2) obtained from pivalaldehyde and glycine amides are resolved efficiently by crystallization of diastereomeric ammonium salts with chiral acids (mandelates and a gulonate respectively).The free bases are acylated under Schotten-Baumann conditions to give enantiomerically pure 1-Bz-, 1-BOC-, 1-Z- or 1-formyl-2-t-butyl-3-methyl- or -3-benzyl-4-imidazolidinones.Diastereoselective alkylation of the 3-methyl derivatives (BMI) with a variety of electrophiles (LDA/THF -70 to +25 degC) gives trans-disubstituted imidazolidinones exclusively (3-22).Some of these are hydrolyzed by a procedure employing excess acidic ion exchange resin to give enantiomerically pure (R)- or (S)-amino acids.The procedure is compared with other methods of generating chiral glycine enolates.
- Fitzi, Robert,Seebach, Dieter
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p. 5277 - 5292
(2007/10/02)
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- Synthesis of Enantio- and Diastereo-isomerically Pure β- and γ-Substituted Glutamic Acids via Glycine Condensation with Activated Olefins
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The glycine fragment in the nickel(II) complex formed from the Schiff base of glycine and (S)-o-benzophenone undergoes base-catalysed Michael addition in methanol in the presence of MeONa to the activated olefins methyl acrylate, acrylonitrile, methyl methacrylate, acrolein, and methyl trans-cinnamate.Complexes of substituted (S)-glutamic acid or its derivatives were formed in good chemical yields with almost complete diastereoselection at the α-carbon atom of the amino acid moiety.Diastereoselection at the β- and γ-atoms was not significant, but the isomeric complexes could be easily separated chromatogrphically.Cleavage of the pure diastereoisomers with aqueous HCl gave, in good yields, optically pure glutamic acids and regenerated the original chiral reagent.The configurations of the amino acid β- and γ-carbon atoms were determined by 1H n. m. r. spectroscopy and crystal structure X-ray analysis of the corresponding original complexes.The addition to acrolein, catalysed by triethylamine in methanol, leads to the 1,4-adduct exclusively.The amino acid thus obtained could be converted into (S)-proline by reduction with NaBH4.
- Belokon, Yuri N.,Bulychev, Aleksandr G.,Ryzhov, Mikhail G.,Vitt, Sergei V.,Batsanov, Andrei S.,et al.
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p. 1865 - 1872
(2007/10/02)
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