- Enzymatic Regio- And Enantioselective C-H Oxyfunctionalization of Fatty Acids
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Directed evolution of a P450 hydroxylase (P450BSβ) achieves an engineered enzyme that is able to catalyze C-H oxyfunctionalization of fatty acids (FAs) in a highly regio- and enantioselective fashion (>20:1 Cβ/Cα and > 99% ee in all cases). The biocatalyst displays high reactivity (TON up to 1540), takes inexpensive H2O2 as oxidant, and converts C11-C18 saturated FAs as well as naturally derived unsaturated oleic and linoleic acids to optically pure β-hydroxy FAs. Merging biocatalysis with chemical transformation, we further offer a chemoenzymatic strategy to access valuable FA derivatives bearing 1,3-diol, β-amino, β-lactone, and β-lactam functionalities in either enantiomeric form. Molecular docking studies provide a rationale for the regio- and enantioselectivity of this reaction.
- Chen, Hao,Huang, Mengfei,Yan, Wenliang,Bai, Wen-Ju,Wang, Xiqing
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p. 10625 - 10630
(2021/09/02)
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- Structure of the unusual Sinorhizobium fredii HH103 lipopolysaccharide and its role in symbiosis
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Rhizobia are soil bacteria that form important symbiotic associations with legumes, and rhizobial surface polysaccharides, such as K-antigen polysaccharide (KPS) and lipopolysaccharide (LPS), might be important for symbiosis. Previously, we obtained a mutant of Sinorhizobium fredii HH103, rkpA, that does not produce KPS, a homopolysaccharide of a pseudaminic acid derivative, but whose LPS electrophoretic profile was indistinguishable from that of the WT strain. We also previously demonstrated that the HH103 rkpLMNOPQ operon is responsible for 5-acetamido-3,5,7,9-tetradeoxy-7-(3-hydroxybutyramido)-L-glyc-ero-L-manno-nonulosonic acid [Pse5NAc7(3OHBu)] production and is involved in HH103 KPS and LPS biosynthesis and that an HH103 rkpM mutant cannot produce KPS and displays an altered LPS structure. Here, we analyzed the LPS structure of HH103 rkpA, focusing on the carbohydrate portion, and found that it contains a highly heterogeneous lipid A and a peculiar core oligosaccharide composed of an unusually high number of hexuronic acids containing b-configured Pse5NAc7(3OHBu). This pseudaminic acid derivative, in its a-configuration, was the only structural component of the S. fredii HH103 KPS and, to the best of our knowledge, has never been reported from any other rhizobial LPS. We also show that Pse5NAc7(3OHBu) is the complete or partial epitope for a mAb, NB6-228.22, that can recognize the HH103 LPS, but not those of most of the S. fredii strains tested here. We also show that the LPS from HH103 rkpM is identical to that of HH103 rkpA but devoid of any Pse5NAc7(3OHBu) residues. Notably, this rkpM mutant was severely impaired in symbiosis with its host, Macroptilium atropurpureum.
- Di Lorenzo, Flaviana,Speciale, Immacolata,Silipo, Alba,Alías-Villegas, Cynthia,Acosta-Jurado, Sebastián,Rodríguez-Carvajal, Miguel-ángel,Dardanelli, Marta S.,Palmigiano, Angelo,Garozzo, Domenico,Ruiz-Sainz, José-Enrique,Molinaro, Antonio,Vinardell, José-María
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p. 10969 - 10987
(2021/01/07)
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- 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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p. 209 - 217
(2019/03/23)
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- Enantioselective organocatalysis-based synthesis of 3-hydroxy fatty acids and fatty γ-lactones
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3-Hydroxy fatty acids have attracted the interest of researchers, since some of them may interact with free fatty acid receptors more effectively than their non-hydroxylated counterparts and their determination in plasma provides diagnostic information regarding mitochondrial deficiency. We present here the development of a convenient and general methodology for the asymmetric synthesis of 3-hydroxy fatty acids. The enantioselective organocatalytic synthesis of terminal epoxides, starting from long chain aldehydes, is the key-step of our methodology, followed by ring opening with vinylmagnesium bromide. Ozonolysis and subsequent oxidation leads to the target products. MacMillan’s third generation imidazolidinone organocatalyst has been employed for the epoxide formation, ensuring products in high enantiomeric purity. Furthermore, a route for the incorporation of deuterium on the carbon atom carrying the hydroxy group was developed allowing the synthesis of deuterated derivatives, which may be useful in biological studies and in mass spectrometry studies. In addition, the synthesis of fatty γ-lactones, corresponding to 4-hydroxy fatty acids, was also explored.
- Bourboula, Asimina,Limnios, Dimitris,Kokotou, Maroula G.,Mountanea, Olga G.,Kokotos, George
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- Succinct synthesis of saturated hydroxy fatty acids and: In vitro evaluation of all hydroxylauric acids on FFA1, FFA4 and GPR84
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Saturated hydroxy fatty acids make up a class of underexplored lipids with potentially interesting biological activities. We report a succinct and general synthetic route to saturated hydroxy fatty acids hydroxylated at position 6 or higher, and exemplify this with the synthesis of hydroxylauric acids. All regioisomers of hydroxylauric acids were tested on free fatty acid receptors FFA1, FFA4 and GPR84. The results show that the introduction of a hydroxy group and its position have a high impact on receptor activity.
- Kaspersen, Mads Holmgaard,Jenkins, Laura,Dunlop, Julia,Milligan, Graeme,Ulven, Trond
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supporting information
p. 1360 - 1365
(2017/07/07)
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- Correction: Total synthesis of fellutamides, lipopeptide proteasome inhibitors. More sustainable peptide bond formation (Organic and Biomolecular Chemistry (2016) 14 (8367-8375)
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The incorrect graphics for Schemes 3 and 4 were included. The correct schemes are shown below. (Figure Presented). The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers.
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p. 9159 - 9159
(2016/10/11)
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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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- Total synthesis of fellutamides, lipopeptide proteasome inhibitors. More sustainable peptide bond formation
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Solution-phase syntheses of three bioactive natural products of mixed polypeptide-polyketide biogenesis, fellutamides A, B, and C, have been achieved. Three peptide bonds are generated without the use of coupling reagents in each synthesis of the fellutamides, which act against proteasomes.
- Pirrung, Michael C.,Zhang, Fa,Ambadi, Sudhakar,Gangadhara Rao
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p. 8367 - 8375
(2016/09/09)
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- Photobiocatalytic decarboxylation for olefin synthesis
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Here, we describe the combination of OleTJE with a light-driven in situ H2O2-generation system for the selective and quantitative conversion of fatty acids into terminal alkenes. The photobiocatalytic system shows clear advantages regarding enzyme activity and yield, resulting in a simple and efficient system for fatty acid decarboxylation.
- Zachos, Ioannis,Ga?meyer, Sarah Katharina,Bauer, Daniel,Sieber, Volker,Hollmann, Frank,Kourist, Robert
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supporting information
p. 1918 - 1921
(2015/02/05)
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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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- Solution phase synthetic approach to fellutamide B
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Abstract A convenient solution phase approach for the synthesis of fellutamide B with efficient purification techniques has been demonstrated on the molecule for the first time. The strategy involves the use of natural amino acids as starting materials and classical peptide coupling reactions. The synthesis has been achieved in 10 steps with overall yield of 26.7% making the synthesis facile.
- Yadav, Jhillu Singh,Dachavaram, Soma Shekar,Grée, René,Das, Saibal
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supporting information
p. 3999 - 4001
(2015/06/08)
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- Seven new and two known lipopeptides as well as five known polyketides: The activated production of silent metabolites in a marine-derived fungus by chemical mutagenesis strategy using diethyl sulphate
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AD-2-1 is an antitumor fungal mutant obtained by diethyl sulfate mutagenesis of a marine-derived Penicillium purpurogenum G59. The G59 strain originally did not produce any metabolites with antitumor activities in MTT assays using K562 cells. Tracing newly produced metabolites under guidance of MTT assay and TLC analysis by direct comparison with control G59 extract, seven new (1-7) and two known (8-9) lipopeptides were isolated together with five known polyketides 10-14 from the extract of mutant AD-2-1. Structures of the seven new compounds including their absolute configurations were determined by spectroscopic and chemical evidences and named as penicimutalides A-G (1-7). Seven known compounds were identified as fellutamide B (8), fellutamide C (9), 1.-O-methylaverantin (10), averantin (11), averufin (12), nidurufin (13), and sterigmatocystin (14). In the MTT assay, 1-14 inhibited several human cancer cell lines to varying extents. All the bioassays and HPLC-photodiode array detector (PDAD)-UV and HPLC-electron spray ionization (ESI)-MS analyses demonstrated that the production of 1-14 in the mutant AD-2-1 was caused by the activated production of silent metabolites in the original G59 fungal strain. Present results provided additional examples for effectiveness of the chemical mutagenesis strategy using diethyl sulphate mutagenesis to discover new compounds by activating silent metabolites in fungal isolates.
- Wu, Chang-Jing,Li, Chang-Wei,Cui, Cheng-Bin
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p. 1815 - 1838
(2014/06/09)
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- Total synthesis of fellutamide b and deoxy-fellutamides B, C, and D
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The total syntheses of the marine-derived lipopeptide natural product fellutamide B and deoxy-fellutamides B, C, and D are reported. These compounds were accessed through a novel solid-phase synthetic strategy using Weinreb amide-derived resin. As part of the synthesis, a new enantioselective route to (3R)-hydroxy lauric acid was developed utilizing a Brown allylation reaction followed by an oxidative cleavage-oxidation sequence as the key steps. The activity of these natural products, and natural product analogues was also assessed against Mycobacterium tuberculosis in vitro.
- Giltrap, Andrew M.,Cergol, Katie M.,Pang, Angel,Britton, Warwick J.,Payne, Richard J.
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p. 2382 - 2397
(2013/08/23)
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- AMIDE COMPOUND OR SALT THEREOF, AND BIOFILM FORMATION INHIBITOR, BIOFILM REMOVER AND BACTERICIDE EACH USING THE AMIDE COMPOUND OR SALT THEREOF
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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 biofilm. 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 15
(2009/07/18)
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- Neurotrophic peptide aldehydes: Solid phase synthesis of fellutamide B and a simplified analog
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A combination of solid phase and solution phase synthetic methods have been used to complete the total synthesis of the neurotrophic lipopeptide aldehyde fellutamide B (2). The β-hydroxy aliphatic tail was prepared by regioselective reductive opening of a cyclic sulfate, and later coupled to a solid phase resin. The synthetic compound was then examined in cytotoxicity and nerve growth factor (NGF) induction assays. A simplified analog of fellutamide B also showed activity.
- Schneekloth Jr., John S.,Sanders, John L.,Hines, John,Crews, Craig M.
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p. 3855 - 3858
(2007/10/03)
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- Studies towards lipid A: a synthetic strategy for the enantioselective preparation of 3-hydroxy fatty acids
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A short and efficient enantioselective synthesis of (R)-3-hydroxydodecanoic acid is described, involving a Sharpless asymmetric dihydroxylation to produce the required (R)-stereochemistry.
- Guaragna, Annalisa,Nisco, Mauro De,Pedatella, Silvana,Palumbo, Giovanni
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p. 2839 - 2841
(2007/10/03)
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- Aminoalkyl glucosamine phosphate compounds and their use as adjuvants and immunoeffectors
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Aminoalkyl glucosamine phosphate compounds that are adjuvants and immunoeffectors are described and claimed. The compounds have a 2-deoxy-2-amino glucose in glycosidic linkage with an aminoalkyl (aglycon) group. Compounds are phosphorylated at the 4 or 6 carbon on the glucosamine ring and comprise three 3-alkanoyloxyalkanoyl residues. The compounds augment antibody production in immunized animals as well as stimulate cytokine production and activate macrophages. Methods for using the compounds as adjuvants and immunoeffectors are also disclosed.
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Page column 10
(2008/06/13)
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- Absolute configuration of aflastatin A, a specific inhibitor of aflatoxin production by Aspergillus parasiticus
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Aflastatin A (1) is a specific inhibitor of aflatoxin production by Aspergillus parasiticus. It has the novel structure of a tetramic acid derivative with a long alkyl side chain. The absolute configurations of 29 chiral centers contained in I were chemically elucidated in this study. First, four small fragment molecules were prepared from I or its methyl ether (2), and their absolute structures were assigned as N-methyl-D-alanine, (2S,4R)-2,4-dimethyl-1,6-hexanediol dibenzoate, (R)-3-hydroxydodecanoic acid, and (R)-1,2,4-butanetriol tribenzoate. Next, an acyclic fragment molecule 3 with 13 chiral centers was obtained from I by NaIO4 oxidation, and its relative stereochemistry was elucidated by J-based configuration analysis. By analyzing coupling constants of 3J(H,H) and 2,3J(C,H) and ROE data, the relative configuration of 3 was verified. Finally, by further J-based configuration analysis using a fragment molecule 7 prepared from 2 with 28 chiral carbons, all relative configurations in the alkyl side chain of I were clarified. By connecting these relative configurations with the absolute configurations of first four fragment molecules, the absolute stereochemistry of 1 was fully determined.
- Ikeda, Hiroyuki,Matsumori, Nobuaki,Ono, Makoto,Suzuki, Akinori,Isogai, Akira,Nagasawa, Hiromichi,Sakuda, Shohei
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p. 438 - 444
(2007/10/03)
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- Fellutamides A and B, cytotoxic peptides from a marine fish-possessing fungus Penicillium fellutanum
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Two cytotoxic peptides, fellutamides A and B, have been isolated from the cultured fungus Penicillium fellutanum Biourge which was isolated from the gastrointestine of the marine fish Apogon endekataenia Bleeker, and the structures were elucidated to be 1 and 2 by two-dimensional NMR and FAB MS/MS data.
- Shigemori,Wakuri,Yazawa,Nakamura,Sasaki,Kobayashi
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p. 8529 - 8534
(2007/10/02)
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- Asymmetric Reduction of Aliphatic Short- to Long-Chain β-Keto Acids by Use of Fermenting Bakers' Yeast
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Eleven β-keto acids, ranging from 3-oxobutanoic to 3-oxooctanoic acids, were reduced with fermenting bakers' yeast to the corresponding optically active β-hydroxy acids, which were isolated as the methyl esters.In all cases, the (R)-hydroxy acids were obtained in >/=98percent ee, except for 3-oxobutanoic acid, which afforded the (S)-hydroxy acid in 86percent ee.Inhibition of fermentation was observed for 3-oxoundecanoic to 3-oxotetradecanoic acids, leading to no reduction.Lowering of the substrate concentration was found to be appreciably effective in avoiding inhibition.
- Utaka, Masanori,Watabu, Hisashi,Higashi, Hiroshi,Sakai, Takashi,Tsuboi, Sadao,Torii, Sigeru
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p. 3917 - 3921
(2007/10/02)
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- New potential immunoenhancing compounds. Synthesis and pharmacological evaluation of new long-chain 2-amido-2-deoxy-D-glucose derivatives
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A series of long-chain fatty acids and the corresponding 2-hydroxy, 2-oxo, 3-hydroxy acid glucosamides were evaluated as immunomodulating compounds. In a preliminary screening, 2-[(2-ethoxycarbonyloxy)tetradecanoyl-amino]-2-deoxy-D-glucose (2b) and 2-(3-hydroxydodecanoyl-amino)-2-deoxy-D-glucose (5a) resulted to be the most effective in enhancing the glucosamine activity. The findings of in vitro-ex vivo tests (unidirectional mixed lymphocyte culture reaction and primary antibody production) and in vivo tests (delayed type hypersensitivity, protection against bacterial or fungal infection and against Sarcoma 180 or Lewis lung carcinoma transplants) were very encouraging and allowed to assume for the two substances a protective activity, presumably through the ability of activating phagocytic and NK cells.
- Valcavi,Albertoni,Brandt,Corsi,Farina,Foresta,Pascucci,Ramacci
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p. 1190 - 1195
(2007/10/02)
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- The Preparation of Optically Pure 3-Hydroxyalkanoic Acid. The Enantioface-differentiating Hydrogenation of the C=O Double Bond with Modified Raney Nickel. XXXVII
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The enantioface-differentiating hydrogenation of methyl 3-oxoalkanoate (CH3(CH2)nCOCH2COOCH3, n=0, 6, 8, 10, 12) over the (R,R)-tartaric acid-NaBr-modified Raney nickel catalyst ((R,R)-TA-NaBr-MRNi) gave methyl (R)-3-hydroxyalkanoate (CH3(CH2)nCH(OH)CH2COOCH3, n=0, 6, 8, 10, 12) in an average optical yield of 85percent.After the methyl ester had been converted to dicyclohexylammonium salt of 3-hydroxyalkanoic acid, the salt was recrystallized three times from acetonitrile and then treated with acid to give optically pure (R)-3-hydroxyalkanoic acid (CH3(CH2)nCH(OH)CH2COOH, n=0, 6, 8, 10, 12) in a reasonable yield.From the hydrogenation product with (S,S)-TA-NaBr-MRNi, optically pure (S)-3-hydroxyalkanoic acid was obtained by the same process as above.
- Nakahata, Masaaki,Imaida, Motomasa,Ozaki, Hiroshi,Harada, Tadao,Tai, Akira
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p. 2186 - 2189
(2007/10/02)
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- THE ABSOLUTE CONFIGURATION OF THE ACETYLENIC COMPOUND FALCARINDIOL
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Key Word Index-Peucedanum oreoselinum; Umbelliferae; falcarindiol; (R)-heptadecan-8-ol; (S)-heptadecan-8-ol; (3R,8S)-heptadecan-3,8-diol.Abstract-The absolute configuration of the acetylenic compound falcarindiol is established as (3R,8S) and falcarindiol is thus (+)-(3R,8S)-(Z)-heptadeca-1,9-dien-4,6-diyn-3,8-diol. (R)-Heptadecan-8-ol and (S)-heptadecan-8-ol are synthesized and (3R,8S)-heptadecan-3,8-diol is characterized.
- Lemmich, Else
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p. 1419 - 1420
(2007/10/02)
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