- Rapid and Selective Chemical Editing of Ribosomally Synthesized and Post-Translationally Modified Peptides (RiPPs) via CuII-Catalyzed β-Borylation of Dehydroamino Acids
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We report the fast and selective chemical editing of ribosomally synthesized and post-translationally modified peptides (RiPPs) by β-borylation of dehydroalanine (Dha) residues. The thiopeptide thiostrepton was modified efficiently using CuII-catalysis under mild conditions and 1D/2D NMR of the purified product showed site-selective borylation of the terminal Dha residues. Using similar conditions, the thiopeptide nosiheptide, lanthipeptide nisin Z, and protein SUMO_G98Dha were also modified efficiently. Borylated thiostrepton showed an up to 84-fold increase in water solubility, and minimum inhibitory concentration (MIC) assays showed that antimicrobial activity was maintained in thiostrepton and nosiheptide. The introduced boronic-acid functionalities were shown to be valuable handles for chemical mutagenesis and in a reversible click reaction with triols for the pH-controlled labeling of RiPPs.
- de Vries, Reinder H.,Viel, Jakob H.,Kuipers, Oscar P.,Roelfes, Gerard
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supporting information
p. 3946 - 3950
(2020/12/25)
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- Switching Lysophosphatidylserine G Protein-Coupled Receptor Agonists to Antagonists by Acylation of the Hydrophilic Serine Amine
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Three human G protein-coupled receptors (GPCRs)—GPR34/LPS1, P2Y10/LPS2, and GPR174/LPS3—are activated specifically by lysophosphatidylserine (LysoPS), an endogenous hydrolysis product of a cell membrane component, phosphatidylserine (PS). LysoPS consists of-serine, glycerol, and fatty acid moieties connected by phosphodiester and ester linkages. We previously generated potent and selective GPCR agonists by modification of the three modules and the ester linkage. Here, we show that a novel modification of the hydrophilic serine moiety, that is, N-acylations of the serine amine, converted a GPR174 agonist to potent GPR174 antagonists. Structural exploration of the amide functionality provided access to a range of activities from agonist to partial agonist to antagonist. The present study would provide a new strategy for the development of lysophospholipid receptor antagonists.
- Sayama, Misa,Uwamizu, Akiharu,Ikubo, Masaya,Chen, Luying,Yan, Ge,Otani, Yuko,Inoue, Asuka,Aoki, Junken,Ohwada, Tomohiko
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p. 10059 - 10101
(2021/07/28)
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- Synthesis method and application of 1-aza -5-germanium-5-alkyl bicyclic [3.3.3] undecane compound.
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The invention provides a 1-aza-5-germanium hetero-5-alkyl bicyclic [3.3.3] hendecane compound having a structure shown in the formula I, and the types of the 1-aza-5-germanium hetero-5-alkyl bicyclic[3.3.3] hendecane compound are expanded. The provided compound can serve as a nucleophilic reagent, the air and humidity conditions of the nucleophilic reagent are stable, and the efficiency of the Ge-Stille coupling reaction of aryl halogen and the 1-aza-5-germanium hetero-5-alkyl bicyclic [3.3.3] hendecane compound is high.
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Paragraph 0235; 0240
(2020/05/11)
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- Oxidative Damage in Aliphatic Amino Acids and Di- and Tripeptides by the Environmental Free Radical Oxidant NO3?: the Role of the Amide Bond Revealed by Kinetic and Computational Studies
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Kinetic and computational data reveal a complex behavior of the important environmental free radical oxidant NO3? in its reactions with aliphatic amino acids and di- and tripeptides, suggesting that attack at the amide N-H bond in the peptide backbone is a highly viable pathway, which proceeds through a proton-coupled electron transfer (PCET) mechanism with a rate coefficient of about 1 × 106 M-1 s-1 in acetonitrile. Similar rate coefficients were determined for hydrogen abstraction from the α-carbon and from tertiary C-H bonds in the side chain. The obtained rate coefficients for the reaction of NO3? with aliphatic di- and tripeptides suggest that attack occurs at all of these sites in each individual amino acid residue, which makes aliphatic peptide sequences highly vulnerable to NO3?-induced oxidative damage. No evidence for amide neighboring group effects, which have previously been found to facilitate radical-induced side-chain damage in phenylalanine, was found for the reaction of NO3? with side chains in aliphatic peptides.
- Nathanael, Joses G.,Wille, Uta
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p. 3405 - 3418
(2019/03/11)
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- Industrial preparation method of lacosamide
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The invention relates to an industrial preparation method of lacosamide. Esterification is performed on D-serine for generating D-serine methyl ester hydrochloride; the D-serine methyl ester hydrochloride reacts with acetyl chloride for generating N-acetyl-D-serine methyl ester; the N-acetyl-D-serine methyl ester reacts with benzylamine for obtaining (R)-2-acetamido-N-benzyl-3-hydroxypropionamide;the (R)-2-acetamido-N-benzyl-3-hydroxypropionamide reacts with methyl p-toluenesulfonate under an alkaline condition for obtaining (R)-2-acetamido-N-benzyl-3-methoxypropionamide. The preparation method provide by the invention has relatively mild reaction conditions in each steps; the raw materials are easy to obtain; no high-toxicity reagent is used; a safe and environment-friendly green chemistry idea is met; and the method is suitable for industrial amplification.
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Paragraph 0018; 0021; 0022; 0027
(2018/03/26)
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- 1,1-Diacyloxy-1-phenylmethanes as versatile N-acylating agents for amines
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1,1-Diacyloxy-1-phenylmethanes and 1-pivaloxy-1-acyloxy-1-phenylmethanes have been used as bench stable N-acylating reagents for primary and secondary amines and anilines under solvent-free conditions to afford their corresponding amides in good yield.
- Chapman, Robert. S.L.,Tibbetts, Joshua. D.,Bull, Steven. D.
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p. 5330 - 5339
(2018/06/15)
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- Formyloxyacetoxyphenylmethane and 1,1-diacylals as versatile O-formylating and O-acylating reagents for alcohols
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Formyloxyacetoxyphenylmethane, symmetric 1,1-diacylals and mixed 1-pivaloxy-1-acyloxy-1-phenylmethanes have been used as moisture stable O-formylating and O-acylating reagents for primary and secondary alcohols, allylic alcohols and phenols under solvent/catalyst free conditions to afford their corresponding esters in good yield.
- Chapman, Robert S.L.,Francis, Molly,Lawrence, Ruth,Tibbetts, Joshua D.,Bull, Steven D.
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p. 6442 - 6452
(2018/10/02)
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- Process for the preparation of lacosamide
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A novel process for the preparation of (R)-2-acetamido-N-benzyl-3-methoxypropionamide (Lacosamide) is described. It comprises reacting N-acetyl-D-serine methyl ester with benzylamine catalyzed by a non-nucleophilic base to obtain (R)-2-acetamido-2-N-benzyl-3-hydroxy propionamide followed by its methylation.
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Page/Page column 11; 12
(2016/10/17)
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- Observations concerning the synthesis of tryptamine homologues and branched tryptamine derivatives via the borrowing hydrogen process: Synthesis of psilocin, bufotenin, and serotonin
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Observations concerning the synthesis of substituted tryptamine derivatives starting from indoles and 1,n-amino alcohols via the borrowing hydrogen process are discussed. This catalytic, single-step, and modular approach to tryptamines and homotryptamines allows the synthesis of branched and nonbranched tryptamines as well as tryptamine-based natural products such as psilocin, bufotenin, and serotonin.
- Bartolucci, Silvia,Mari, Michele,Di Gregorio, Giovanni,Piersanti, Giovanni
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p. 2233 - 2238
(2016/04/19)
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- Comparison of liquid chromatography-isotope ratio mass spectrometry (LC/IRMS) and gas chromatography-combustion-isotope ratio mass spectrometry (GC/C/IRMS) for the determination of collagen amino acid δ13C values for palaeodietary and palaeoecological reconstruction
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Results are presented of a comparison of the amino acid (AA) δ13C values obtained by gas chromatography-combustion-isotope ratio mass spectrometry (GC/C/IRMS) and liquid chromatography-isotope ratio mass spectrometry (LC/IRMS). Although the primary focus was the compound-specific stable carbon isotope analysis of bone collagen AAs, because of its growing application for palaeodietary and palaeoecological reconstruction, the results are relevant to any field where AA δ13C values are required. We compare LC/IRMS with the most up-to-date GC/C/IRMS method using N-acetyl methyl ester (NACME) AA derivatives. This comparison involves the analysis of standard AAs and hydrolysates of archaeological human bone collagen, which have been previously investigated as N-trifluoroacetyl isopropyl esters (TFA/IP). It was observed that, although GC/C/IRMS analyses required less sample, LC/IRMS permitted the analysis of a wider range of AAs, particularly those not amenable to GC analysis (e.g. arginine). Accordingly, reconstructed bulk δ13C values based on LC/IRMS-derived δ13C values were closer to the EA/IRMS-derived δ13C values than those based on GC/C/IRMS values. The analytical errors for LC/IRMS AA δ13C values were lower than GC/C/IRMS determinations. Inconsistencies in the δ13C values of the TFA/IP derivatives compared with the NACME- and LC/IRMS-derived δ13C values suggest inherent problems with the use of TFA/IP derivatives, resulting from: (i) inefficient sample combustion, and/or (ii) differences in the intra-molecular distribution of δ13C values between AAs, which are manifested by incomplete combustion. Close similarities between the NACME AA δ13C values and the LC/IRMS-derived δ13C values suggest that the TFA/IP derivatives should be abandoned for the natural abundance determinations of AA δ13C values.
- Dunn, Philip J. H.,Honch, Noah V.,Evershed, Richard P.
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experimental part
p. 2995 - 3011
(2012/05/20)
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- Synthesis and anticonvulsant activities of (R)-N-(4′-substituted) benzyl 2-acetamido-3-methoxypropionamides
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The structure-activity relationship (SAR) for the N-benzyl group in the clinical antiepileptic agent (R)-lacosamide [(R)-N-benzyl 2-acetamido-3- methoxypropionamide, (R)-3] has been explored. Forty-three compounds were prepared and then evaluated at the National Institute of Neurological Disorders and Stroke Anticonvulsant Screening Program for seizure protection in the maximal electroshock (MES) and subcutaneous Metrazol models. Comparing activities for two series of substituted aryl regioisomers (2′, 3′, 4′) showed that 4′-modified derivatives had the highest activity. Significantly, structural latitude existed at the 4′-site. The SAR indicated that nonbulky 4′-substituted (R)-3 derivatives exhibited superb activity, independent of their electronic properties. Activities in the MES test of several compounds were comparable with or exceeded that of (R)-3 and surpassed the activities observed for the traditional antiepileptic agents phenytoin, phenobarbital, and valproate. 2009 American Chemical Society.
- Salomé, Christophe,Salomé-Grosjean, Elise,Park, Ki Duk,Morieux, Pierre,Swendiman, Robert,DeMarco, Erica,Stables, James P.,Kohn, Harold
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supporting information; experimental part
p. 1288 - 1305
(2010/07/10)
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- Synthesis and evaluation of dihydroimidazolo and dihydrooxazolo ring-fused 2-pyridones-targeting pilus biogenesis in uropathogenic bacteria
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Dihydrothiazolo ring-fused 2-pyridones have previously been shown to inhibit pilus assembly in uropathogenic Escherichia coli. Methods have now been developed to synthesize both dihydroimidazolo and dihydrooxazolo ring-fused 2-pyridones. To obtain the nitrogen analogs, Cbz-protected imidazolines were reacted with an acyl-Meldrum's acid derivative under acidic conditions. To prepare the oxygen analogs, a one-pot procedure was developed that allowed synthesis of dihydrooxazolo ring-fused 2-pyridones starting from acylated serine derivatives. After hydrolysis to their corresponding carboxylic acids and lithium carboxylates, biological evaluation revealed that the sulfur could be replaced by an oxygen atom and still maintains the ability to inhibit pilus assembly in uropathogenic E. coli. However, introducing a secondary amine instead of oxygen resulted in a substantial decrease in biological activity.
- Pemberton, Nils,Pinkner, Jerome S.,Edvinsson, Sofie,Hultgren, Scott J.,Almqvist, Fredrik
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p. 9368 - 9376
(2008/12/22)
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- ANTI-ODOR COMPOSITIONS AND THERAPEUTIC USE
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This application discloses a composition comprising a malodor compound and an anti-odor ingredient effective for reducing the presence or production of malodor. The composition may be topically applied to a subject and is useful for cosmetic conditions, pharmaceutical indications, or other objectives.
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- Conversion of isomeric 2:3 adducts (aminoacid-formaldehyde) to N-acyl-pseudoprolines derivatives
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Reaction of acyl chlorides or acid anhydrides with isomeric 2:3 adducts derived from condensation of l-serine (1a), l-threonine (1b) and l-cysteine (1c) methyl esters with formaldehyde afforded N-acyl-pseudoprolines 7-19 in various yields. These 2:3 adducts can be considered as synthetic equivalents of oxaproline and thiaproline moieties. The present work revealed the versatile behaviour of the two 2:3 adducts as a consequence of the ring-chain tautomerism occurring in the five- and/or seven-membered rings.
- Sélambarom, Jimmy,Smadja, Jacqueline,Pavia, André A.
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p. 615 - 617
(2007/10/03)
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- Microwave-assisted ring expansion of N-acetyl 3′-unsubstituted aziridine in the presence of Lewis acids
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The microwave-assisted ring expansion of N-acetyl 3′-unsubstituted aziridine-2-imides and N-acetyl 3′-unsubstituted aziridine-2-esters to oxazolines is reported. The regioselectivities of the rearrangements depend upon the reaction conditions, such as the Lewis acid selected and the solvent.
- Cardillo,Gentilucci,Gianotti,Tolomelli
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p. 2807 - 2812
(2007/10/03)
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- Intramolecular Photoreaction of Synthetic Oligopeptide-Linked Anthraquinone Molecules
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Photoreaction of (N-acetylglycyl)oligopeptide-linked anthraquinone molecules was investigated.In an acetonitrile solution, the photoexcited anthraquinone moiety abstracted intramolecularly the hydrogen atom of the methylene site of glycine residue.The biradical formed was followed by the formation of C-O bonding via radical recombination to produce ring-closure products in high yields (23-58percent).A variety of oligopeptide spacers between acetylglycine and anthraquinone moieties were systematically changed, and their photoreactivities were investigated.The isolated ring-closure products showed a site-selectivity in the photoreaction; one of the carbonyl groups of anthraquinone moiety coupled with the methylene group predominantly (the selectivity was 88/12-100/0).The efficiency of the photocyclization was dependent upon the size and the sequence of the oligopeptide spacer.These results showed that the oligopeptide spacer might control the distance and the orientation among the reaction sites, glycine methylene, and anthraquinone carbonyl groups.
- Maruyama, Kazuhiro,Hashimoto, Masakazu,Tamiaki, Hitoshi
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p. 6143 - 6150
(2007/10/02)
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- Acetylation under ultrasonic conditions: Convenient preparation of N-acetylamino acids
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An efficient and simple method of preparation of acetylamino acids from amino acids under ultrasonic conditions is described. The reactions proceed without racemization and the yields are almost quantitative.
- Veera Reddy,Ravindranath
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p. 257 - 264
(2007/10/02)
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