- Rhamnolipid inspired lipopeptides effective in preventing adhesion and biofilm formation of Candida albicans
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Rhamnolipids are biodegradable low toxic biosurfactants which exert antimicrobial and anti-biofilm properties. They have attracted much attention recently due to potential applications in areas of bioremediation, therapeutics, cosmetics and agriculture, however, the full potential of these versatile molecules is yet to be explored. Based on the facts that many naturally occurring lipopeptides are potent antimicrobials, our study aimed to explore the potential of replacing rhamnose in rhamnolipids with amino acids thus creating lipopeptides that would mimic or enhance properties of the parent molecule. This would allow not only for more economical and greener production but also, due to the availability of structurally different amino acids, facile manipulation of physico-chemical and biological properties. Our synthetic efforts produced a library of 43 lipopeptides revealing biologically more potent molecules. The structural changes significantly increased, in particular, anti-biofilm properties against Candida albicans, although surface activity of the parent molecule was almost completely abolished. Our findings show that the most active compounds are leucine derivatives of 3-hydroxy acids containing benzylic ester functionality. The SAR study demonstrated a further increase in activity with aliphatic chain elongation. The most promising lipopeptides 15, 23 and 36 at 12.5 μg/mL concentration allowed only 14.3%, 5.1% and 11.2% of biofilm formation, respectively after 24 h. These compounds inhibit biofilm formation by preventing adhesion of C. albicans to abiotic and biotic surfaces.
- Jovanovic, Milos,Radivojevic, Jelena,O'Connor, Kevin,Blagojevic, Stevan,Begovic, Biljana,Lukic, Vera,Nikodinovic-Runic, Jasmina,Savic, Vladimir
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supporting information
p. 209 - 217
(2019/03/23)
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- Controlling the Regioselectivity of Fatty Acid Hydroxylation (C10) at α- and β-Position by CYP152A1 (P450Bsβ) Variants
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Regioselective hydroxylation on inactivated C?H bonds is among the dream reactions of organic chemists. Cytochrome P450 enzymes (CYPs) perform this reaction in general with high regio- and stereoselectivity (e. g. for steroids as substrates). Furthermore, enzyme engineering may allow to tune the properties of the enzyme. Regioselective hydroxylation of shorter or linear molecules (fatty acids), however, remains challenging even with this enzyme class, due to the high similarity of the substrate's backbone carbons and their conformational flexibility. CYPs hydroxylating fatty acids selectively in the chemically more distinct α- or ω- position are well described. In contrast, selective in-chain hydroxylation of fatty acids lacks precedence. The peroxygenase CYP152A1 (P450Bsβ) is a family member that displays fatty acid hydroxylation at both, the α- and β-position, with preference for the α-position. Herein we report the influence of hydrophobic active site residues on the hydroxylation pattern of this enzyme. By site directed mutagenesis and combination of the libraries, double and triple mutation variants were identified, which hydroxylated decanoic acid (C10) with improved regio-selectivity in the β-position. Variants were identified with a 10-fold increase of the β-regioselectivity (expressed as α/β-ratio) compared to the wild type. In total 103 variants of CYP152A1 (P450Bsβ) were investigated.
- Hammerer, Lucas,Friess, Michael,Cerne, Jeyson,Fuchs, Michael,Steinkellner, Georg,Gruber, Karl,Vanhessche, Koenraad,Plocek, Thomas,Winkler, Christoph K.,Kroutil, Wolfgang
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p. 5642 - 5649
(2019/11/03)
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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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- A Continuous, Fluorogenic Sirtuin 2 Deacylase Assay: Substrate Screening and Inhibitor Evaluation
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Sirtuins are important regulators of lysine acylation, which is implicated in cellular metabolism and transcriptional control. This makes the sirtuin class of enzymes interesting targets for development of small molecule probes with pharmaceutical potential. To achieve detailed profiling and kinetic insight regarding sirtuin inhibitors, it is important to have access to efficient assays. In this work, we report readily synthesized fluorogenic substrates enabling enzyme-economical evaluation of SIRT2 inhibitors in a continuous assay format as well as evaluation of the properties of SIRT2 as a long chain deacylase enzyme. Novel enzymatic activities of SIRT2 were thus established in vitro, which warrant further investigation, and two known inhibitors, suramin and SirReal2, were profiled against substrates containing ε-N-acyllysine modifications of varying length.
- Galleano, Iacopo,Schiedel, Matthias,Jung, Manfred,Madsen, Andreas S.,Olsen, Christian A.
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p. 1021 - 1031
(2016/02/23)
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- Characterization of FabG and FabI of the Streptomyces coelicolor dissociated fatty acid synthase
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Streptomyces coelicolor produces fatty acids for both primary metabolism and for biosynthesis of the secondary metabolite undecylprodiginine. The first and last reductive steps during the chain elongation cycle of fatty acid biosynthesis are catalyzed by FabG and FabI. The S. coelicolor genome sequence has one fabI gene (SCO1814) and three likely fabG genes (SCO1815, SCO1345, and SCO1846). We report the expression, purification, and characterization of the corresponding gene products. Kinetic analyses revealed that all three FabGs and FabI are capable of utilizing both straight and branched-chain β-ketoacyl-NAC and enoyl-NAC substrates, respectively. Furthermore, only SCO1345 differentiates between ACPs from both biosynthetic pathways. The data presented provide the first experimental evidence that SCO1815, SCO1346, and SCO1814 have the catalytic capability to process intermediates in both fatty acid and undecylprodiginine biosynthesis.
- Singh, Renu,Reynolds, Kevin A.
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p. 631 - 640
(2015/03/31)
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- The synthesis of medium-chain-length β-hydroxy esters via the reformatsky reaction
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The synthesis of medium-chain-length β-hydroxy esters in good yield via the Reformatsky reaction is described. This work will be used as the basis for further investigation of hydroxyalkanoate polymers as potential feedstock for biofuel production.
- Sailer, Miloslav,Dubicki, Krystyn I.,Sorensen, John L.
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- AMIDE COMPOUND OR SALT THEREOF, AND BIOFILM INHIBITOR, BIOFILM REMOVER AND DISINFECTANT CONTAINING THE SAME
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The present invention provides a new amide compound and salt thereof that is capable of inhibiting biofilm formation or removing deposited biofilms. The present invention also provides a biofilm formation inhibitor or a biofilm remover containing the amide compound or salt thereof as an active ingredient. An amide compound or salt thereof according to the present invention is denoted by General Formula (1): wherein R1 is a hydrogen atom or a hydroxyl group, R2 is a C5-12 alkyl group, and Q is a substituent denoted by Formula (Q1) or (Q2), wherein n and m are 0 or 1.
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Page/Page column 9
(2009/04/24)
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- Aldol-type reactions of unmasked iodoacetic acid with carbonyl compounds promoted by samarium diiodide: Efficient synthesis of carboxylic 3-hydroxyacids and their derivatives
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An easy, direct, general, and efficient samarium diiodide-mediated preparation of 3-hydroxyacids 1 in high yield by reaction of different aldehydes or ketones with commercially available iodoacetic acid is described. The application of different esterific
- Concellon, Jose M.,Concellon, Carmen
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p. 4428 - 4432
(2007/10/03)
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- Process for the preparation of hydroxy and amino compounds
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A process for the preparation of hydroxy and amino compounds, in which, in a first step, an aldehyde, ketone or imine is reacted in a Reformatsky reaction with a reactive halogen compound and zinc, in carboxylic esters as solvents, the reactive halogen compound being brought into contact with the zinc at the same time as or after contact with the aldehyde, ketone or imine, and in a second step, the reaction product of the first step is hydrolyzed.
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- Asymmetric Samarium-Reformatsky Reaction of Chiral α-Bromoacetyl-2-oxazolidinones with Aldehydes
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The samarium(II) iodide mediated asymmetric Reformatsky-type reaction of chiral 3-bromoacetyl-2-oxazolidinones with various aldehydes was studied. A series of chiral 4-substituted 2-oxazolidinones 1-3 and 5,5-disubstituted "SuperQuat" oxazolidinones 4-5 were employed as chiral auxiliaries of the α-bromoacetic acid. The reaction of 1 with various aldehydes gave the α-unbranched β-hydroxy carboximides in good yields with high diastereomeric excess values (up to >99% de). The majority of the reaction product derived from 5,5-diphenyl SuperQuat 5 were highly crystallinity; a single recrystallization yielding a diastereomerically pure product with the other diastereomer not detectable by spectroscopic methods. The absolute configurations of the β-hydroxy carboximides were determined by signs of optical rotations of the corresponding known ethyl esters referring to the literature values. Hydrolytic cleavage of the appended of β-hydroxy moieties from the auxiliary SuperQuats was readily achieved under mild conditions using lithium hydroxide; the corresponding carboxylic acids and the returned SuperQuats were obtained in good yields without any evidence of racemization. The first step of the reaction is the reduction of the α-bromo group to produce the samarium enolate, which adds to an aldehyde. The absolute configuration of the adduct (7i) derive from benzaldehyde was found to be R, with the samarium enolate favoring the transition state predicted from chelation control of the reagent; this is in analogy to the discussion that has been used for the corresponding titanium enolate. The stereochemistry of the reaction may be explained by incorporating the Nerz-Stormes-Thornton chair transition structure model.
- Fukuzawa, Shin-Ichi,Matsuzawa, Hiroshi,Yoshimitsu, Shin-Ichi
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p. 1702 - 1706
(2007/10/03)
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- Samarium(II) iodide mediated intermolecular coupling reactions of N,N-dibenzyl-α-haloamides with carbonyl compounds
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Samarium(II) iodide mediated coupling reactions of α-haloamides with carbonyl compounds are found to give N,N-dibenzyl-β-hydroxyamides (4a-i, 5a-i, and 6a) in good yields under mild reaction conditions. The transformation of 4a and 5a to N,N-dibenzyl-3-phenylpropanamide (7) and β-hydroxycarboxylic acid (8), respectively, are described.
- Aoyagi, Yutaka,Asakura, Rie,Kondoh, Nobuko,Yamamoto, Rieko,Kuromatsu, Takeshi,Shimura, Ai,Ohta, Akihiro
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p. 970 - 974
(2007/10/03)
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- Seven new didemnins from the marine tunicate Trididemnum solidum
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Seven new didemnins-didemnins M (1), N (2), X (3) and Y (4), nordidemnin N (5), epididemnin A1 (6), and acyclodidemnin A (7)-were isolated from an extract of the Caribbean tunicate Trididemnum solidum. The structures of these compounds were assigned, based on FABMS, high-field NMR data, and chemical degradation studies. Biological activities of these peptides are also described.
- Sakai, Ryuichi,Stroh, Justin G.,Sullins, David W.,Rinehart, Kenneth L.
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p. 3734 - 3748
(2007/10/02)
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- Method for producing rhamnose
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A method for large-scale production of rhamnose and 3-hydroxydecanoic acid is disclosed comprising the steps of growing microorganisms of Pseudomonas sp. capable of production of high levels of rhamnolipid in a defined culture medium containing vegetable oil. Additional steps include isolating the rhamnolipid from the culture medium, hydrolyzing the rhamnolipid to produce rhamnose and 3-hydroxydecanoic acid, and separating the rhamnose from the acid. Corn oil is the preferred vegetable oil and Pseudomonas aeruginosa is the preferred Pseudomonas sp. Non-limiting concentrations of nitrogen compounds and magnesium compounds and limiting concentrations of iron compounds are additionally preferably included in the culture medium.
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- Novel Cytotoxic cyclic depsipeptides from the tunicate trididemnum solidum
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Novel didemnin compounds named didemnin X and didemnin Y have been isolated from the Caribbean tunicate Trididemnum solidum. These compounds have cytotoxic activity and, therefore, are useful as antitumor drugs.
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- The Reaction of Trialkylvinylborate with Carbon Dioxide. A New Method for the Preparation of β-Hydroxycarboxylic Acids from Alkenes
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Chloromagnesium trialkylvinylborate, (R3BCH=CH2)MgCl, on reaction with carbon dioxide under pressure, followed by oxidation with alkaline hydrogen peroxide, gives a β-hydroxycarboxylic acid.
- Deng, Min-Zhi,Lu, Ding-An,Xu, Wei-Hua
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p. 1478 - 1479
(2007/10/02)
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