- Stalobacin: Discovery of Novel Lipopeptide Antibiotics with Potent Antibacterial Activity against Multidrug-Resistant Bacteria
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A novel lipopeptide antibiotic, stalobacin I (1), was discovered from a culture broth of an unidentified Gram-negative bacterium. Stalobacin I (1) had a unique chemical architecture composed of an upper and a lower half peptide sequence, which were linked via a hemiaminal methylene moiety. The sequence of 1 contained an unusual amino acid, carnosadine, 3,4-dihydroxyariginine, 3-hydroxyisoleucine, and 3-hydroxyaspartic acid, and a novel cyclopropyl fatty acid. The antibacterial activity of 1 against a broad range of drug-resistant Gram-positive bacteria was much stronger than those of last resort antibiotics such as vancomycin, linezolid, and telavancin (MIC 0.004-0.016 μg/mL). Furthermore, compound 1 induced a characteristic morphological change in Gram-positive and Gram-negative strains by inflating the bacterial cell body. The absolute configuration of a cyclopropyl amino acid, carnosadine, was determined by the synthetic study of its stereoisomers, which was an essential component for the strong activity of 1.
- Matsui, Kouhei,Matsui, Kouhei,Kan, Yukiko,Kikuchi, Junko,Matsushima, Keisuke,Takemura, Miki,Maki, Hideki,Kozono, Iori,Ueda, Taichi,Minagawa, Kazuyuki
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supporting information
p. 6090 - 6095
(2020/07/10)
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- Ambiguity of NRPS Structure Predictions: Four Bidentate Chelating Groups in the Siderophore Pacifibactin
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Identified through a bioinformatics approach, a nonribosomal peptide synthetase gene cluster in Alcanivorax pacificus encodes the biosynthesis of the new siderophore pacifibactin. The structure of pacifibactin differs markedly from the bioinformatic prediction and contains four bidentate metal chelation sites, atypical for siderophores. Genome mining and structural characterization of pacifibactin is reported herein, as well as characterization of pacifibactin variants accessible due to a lack of adenylation domain fidelity during biosynthesis. A spectrophotometric titration of pacifibactin with Fe(III) and 13C NMR spectroscopy of the Ga(III)-pacifibactin complex establish 1:1 metal:pacifibactin coordination and reveal which of the bidentate binding groups are coordinated to the metal. The photoreaction of Fe(III)-pacifibactin, resulting from Fe(III) coordination of the β-hydroxyaspartic acid ligands, is reported.
- Hardy, Clifford D.,Butler, Alison
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p. 990 - 997
(2019/03/26)
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- Poecillastrin E, F, and G, cytotoxic chondropsin-type macrolides from a marine sponge Poecillastra sp.
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Poecillastrin E (1), F (2), and G (3) were isolated from a marine sponge Poecillastra sp. as the cytotoxic constituents. Their planar structures were determined by analyzing the MS and NMR spectra. They are closely related to the known poecillastrin C (4). The absolute configuration of the β-hydroxyaspartic acid (OHAsp) residue was determined to be D-threo by Marfey's analysis of the hydrolysate. The mode of lactone ring formation of OHAsp residue in 1–3 was determined by selective reduction of the ester linkage followed by acid hydrolysis.
- Irie, Raku,Hitora, Yuki,Ise, Yuji,Okada, Shigeru,Takada, Kentaro,Matsunaga, Shigeki
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p. 1430 - 1434
(2018/02/13)
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- Discovery of new A- and B-type laxaphycins with synergistic anticancer activity
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Two new cyclic lipopeptides termed laxaphycins B4 (1) and A2 (2) were discovered from a collection of the marine cyanobacterium Hormothamnion enteromorphoides, along with the known compound laxaphycin A. The planar structures were solved based on a combined interpretation of 1D and 2D NMR data and mass spectral data. The absolute configurations of the subunits were determined by chiral LC-MS analysis of the hydrolysates, advanced Marfey's analysis and 1D and 2D ROESY experiments. Consistent with similar findings on other laxaphycin A- and B-type peptides, laxaphycin B4 (1) showed antiproliferative effects against human colon cancer HCT116 cells with IC50 of 1.7 μM, while laxaphycins A and A2 (2) exhibited weak activities. The two major compounds isolated from the sample, laxaphycins A and B4, were shown to act synergistically to inhibit the growth of HCT116 colorectal cancer cells.
- Cai, Weijing,Matthew, Susan,Chen, Qi-Yin,Paul, Valerie J.,Luesch, Hendrik
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p. 2310 - 2319
(2018/04/02)
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- Isolation and amino acid sequence of a dehydratase acting on D-erythro-3- hydroxyaspartate from Pseudomonas sp. N99, and its application in the production of optically active 3-hydroxyaspartate
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An enzyme catalyzing the ammonia-lyase reaction for the conversion of D-erythro-3-hydroxyaspartate to oxaloacetate was purified from the cell-free extract of a soil-isolated bacterium Pseudomonas sp. N99. The enzyme exhibited ammonia-lyase activity toward L-threo-3-hydroxyaspartate and D-erythro-3- hydroxyaspartate, but not toward other 3-hydroxyaspartate isomers. The deduced amino acid sequence of the enzyme, which belongs to the serine/ threonine dehydratase family, shows similarity to the sequence of L-threo-3-hydroxyaspartate ammonia- lyase (EC 4.3.1.16) from Pseudomonas sp. T62 (74%) and Saccharomyces cerevisiae (64%) and serine racemase from Schizosaccharomyces pombe (65%). These results suggest that the enzyme is similar to L-threo-3-hydroxyaspartate ammonia-lyase from Pseudomonas sp. T62, which does not act on D-erythro-3-hydroxyaspartate. We also then used the recombinant enzyme expressed in Escherichia coli to produce optically pure L-erythro-3-hydroxyaspartate and D-threo-3-hydroxyaspartate from the corresponding DL-racemic mixtures. The enzymatic resolution reported here is one of the simplest and the first enzymatic method that can be used for obtaining optically pure L-erythro-3-hydroxyaspartate.
- Nagano, Hiroyuki,Shibano, Kana,Matsumoto, Yu,Yokota, Atsushi,Wada, Masaru
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p. 1156 - 1164
(2017/05/29)
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- Rapid chemoenzymatic route to glutamate transporter inhibitor l-TFB-TBOA and related amino acids
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The complex amino acid (l-threo)-3-[3-[4-(trifluoromethyl)benzoylamino]benzyloxy]aspartate (l-TFB-TBOA) and its derivatives are privileged compounds for studying the roles of excitatory amino acid transporters (EAATs) in regulation of glutamatergic neurotransmission, animal behavior, and in the pathogenesis of neurological diseases. The wide-spread use of l-TFB-TBOA stems from its high potency of EAAT inhibition and the lack of off-target binding to glutamate receptors. However, one of the main challenges in the evaluation of l-TFB-TBOA and its derivatives is the laborious synthesis of these compounds in stereoisomerically pure form. Here, we report an efficient and step-economic chemoenzymatic route that gives access to enantio- and diastereopure l-TFB-TBOA and its derivatives at multigram scale.
- Fu, Haigen,Younes, Sabry H. H.,Saifuddin, Mohammad,Tepper, Pieter G.,Zhang, Jielin,Keller, Erik,Heeres, André,Szymanski, Wiktor,Poelarends, Gerrit J.
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supporting information
p. 2341 - 2344
(2017/03/20)
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- Total synthesis and biological evaluation of rakicidin A and discovery of a simplified bioactive analogue
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We report a concise asymmetric synthesis of rakicidin A, a macrocyclic depsipeptide that selectively inhibits the growth of hypoxic cancer cells and stem-like leukemia cells. Key transformations include a diastereoselective organocatalytic cross-aldol reaction to build the polyketide portion of the molecule, a highly hindered ester fragment coupling reaction, an efficient Helquist-type Horner - Wadsworth - Emmons (HWE) macrocyclization, and a new DSC-mediated elimination reaction to construct the sensitive APD portion of rakicidin A. We further report the preparation of a simplified structural analogue (WY1) with dramatically enhanced hypoxia-selective activity. Take my breath away: Rakicidin A, a depsipeptide natural product with hypoxia-selective antitumour activity, is comprised of a ring system containing sensitive and congested functionalities. A modular asymmetric synthesis and initial biological evaluation of the natural product, and the discovery of a simplified analogue displaying strongly enhanced hypoxia selectivity is reported.
- Tsakos, Michail,Clement, Lise L.,Schaffert, Eva S.,Olsen, Frank N.,Rupiani, Sebastiano,Djurhuus, Rasmus,Yu, Wanwan,Jacobsen, Kristian M.,Villadsen, Nikolaj L.,Poulsen, Thomas B.
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supporting information
p. 1030 - 1035
(2016/01/20)
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- Variochelins, Lipopeptide Siderophores from Variovorax boronicumulans Discovered by Genome Mining
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Photoreactive siderophores have a major impact on the growth of planktonic organisms. To date, these molecules have mainly been reported from marine bacteria, although evidence is now accumulating that some terrestrial bacteria also harbor the biosynthetic potential for their production. In this paper, we describe the genomics-driven discovery and characterization of variochelins, lipopeptide siderophores from the bacterium Variovorax boronicumulans, which thrives in soil and freshwater habitats. Variochelins are different from most other lipopeptide siderophores in that their biosynthesis involves a polyketide synthase. We demonstrate that the ferric iron complex of variochelin A possesses photoreactive properties and present the MS-derived structures of two degradation products that emerge upon light exposure.
- Kurth, Colette,Schieferdecker, Sebastian,Athanasopoulou, Kalliopi,Seccareccia, Ivana,Nett, Markus
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p. 865 - 872
(2016/05/24)
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- Stellettapeptins A and B, HIV-inhibitory cyclic depsipeptides from the marine sponge Stelletta sp.
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Two new HIV-inhibitory depsipeptides, stellettapeptins A (1) and B (2), were isolated from an extract of the marine sponge Stelletta sp., collected from northwestern Australia. Structures of these cyclic nonribosomal peptides were elucidated on the basis of extensive NMR data analysis, and chemical degradation and derivatization studies. Stellettapeptins contain numerous nonproteinogenic amino acid residues and they are the first peptides reported to contain a 3-hydroxy-6,8-dimethylnon-4-(Z)-enoic acid moiety. Compounds 1 and 2 potently inhibit infection of human T-lymphoblastoid cells by HIV-1RF with EC50 values of 23 and 27 nM, respectively.
- Shin, Hee Jae,Rashid, Mohammad A.,Cartner, Laura K.,Bokesch, Heidi R.,Wilson, Jennifer A.,McMahon, James B.,Gustafson, Kirk R.
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supporting information
p. 4215 - 4219
(2015/06/22)
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- Complete stereochemistry and preliminary structure-activity relationship of rakicidin A, a hypoxia-selective cytotoxin from micromonospora sp.
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The complete stereochemistry of rakicidin A, a hypoxia-selective cytotoxin produced by Micromonospora sp., was unambiguously established by extensive chemical degradation and derivatization studies. During the PGME derivatization-based configurational analysis of 3-hydroxy-2,4,16-trimethylheptadecanoic acid, an irregular Δδ distribution was observed, which necessitated further acylation of the 3-hydroxy group to resolve the inconsistency. A hydrogenated derivative of rakicidin A, its ring-opened product, and two congeners with different alkyl chain lengths were tested for hypoxia-selective cytotoxicity. The results indicated that both the conjugated diene unit and appropriate chain length are essential for the unique activity of rakicidin A.
- Oku, Naoya,Matoba, Shouhei,Yamazaki, Yohko Momose,Shimasaki, Ryoko,Miyanaga, Satoshi,Igarashi, Yasuhiro
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p. 2561 - 2565
(2015/01/08)
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- Synthesis of a protected derivative of (2R,3R)-β-hydroxyaspartic acid suitable for Fmoc-based solid phase synthesis
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Synthesis of d-threo-hydroxyaspartic acid, orthogonally protected and compatible with an Fmoc solid-phase peptide synthesis strategy is reported. This synthetic procedure starting from (2R,3R)-dimethyltartrate is adaptable to a multi-gram scale. 2,2-Dimethyl-5-oxo-1,3-dioxazolane formation between the β-hydroxy alcohol and the β-carboxylic functions constitutes a key step of the differentiation of the two acidic functions allowing the preparation of (2R,3R)-Fmoc-β-hydroxyaspartic α-allyl ester.
- France, Boyaud,Bruno, Viguier,Nicolas, Inguimbert
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p. 158 - 161
(2013/02/22)
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- A practical synthesis of Nα-Fmoc protected L-threo-β-hydroxyaspartic acid derivatives for coupling via α- Or β-carboxylic group
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A simple and practical general synthetic protocol towards orthogonally protected tHyAsp derivatives fully compatible with Fmoc solid-phase peptide synthetic methodology is reported. Our approach includes enantioresolution of commercially available D,L-tHyAsp racemic mixture by co-crystallization with L-Lys, followed by ion exchange chromatography yielding enantiomerically pure L-tHyAsp and D-tHyAsp, and their selective orthogonal protection. In this way Nα-Fmoc protected tHyAsp derivatives were prepared ready for couplings via either α- or β-carboxylic group onto the resins or the growing peptide chain. In addition, coupling of tHyAsp via β-carboxylic group onto amino resins allows preparation of peptides containing tHyAsn sequences, further increasing the synthetic utility of prepared tHyAsp derivatives. Springer-Verlag 2010.
- Bionda, Nina,Cudic, Mare,Barisic, Lidija,Stawikowski, MacIej,Stawikowska, Roma,Binetti, Diego,Cudic, Predrag
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scheme or table
p. 285 - 293
(2012/08/29)
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- Genomics-driven discovery of taiwachelin, a lipopeptide siderophore from Cupriavidus taiwanensis
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A genome mining study led to the identification of a previously unrecognised siderophore biosynthesis gene cluster in the nitrogen-fixing bacterium Cupriavidus taiwanensis LMG19424. Based upon predicted structural residues, a convenient strategy for an NMR-assisted isolation of the associated metabolite was designed. The structure of the purified siderophore, taiwachelin, was fully characterized by spectroscopic methods and chemical derivatisation.
- Kreutzer, Martin F.,Nett, Markus
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p. 9338 - 9343
(2013/01/15)
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- Structure and biosynthetic assembly of cupriachelin, a photoreactive siderophore from the bioplastic producer cupriavidus necator H16
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The bacterium Cupriavidus necator H16 produces a family of linear lipopeptides when grown under low iron conditions. The structural composition of these molecules, exemplified by the main metabolite cupriachelin, is reminiscent of siderophores that are excreted by marine bacteria. Comparable to marine siderophores, the ferric form of cupriachelin exhibits photoreactive properties. Exposure to UV light induces an oxidation of its peptidic backbone and a concomitant reduction of the coordinated Fe(III). Here, we report the genomics-inspired isolation and structural characterization of cupriachelin as well as its encoding gene cluster, which was identified by insertional mutagenesis. Based upon the functional characterization of adenylation domain specificity, a model for cupriachelin biosynthesis is proposed.
- Kreutzer, Martin F.,Kage, Hirokazu,Nett, Markus
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experimental part
p. 5415 - 5422
(2012/05/20)
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- Perthamides C and D, two new potent anti-inflammatory cyclopeptides from a Solomon Lithistid sponge Theonella swinhoei
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Two new metabolites, perthamides C and D, have been isolated from the marine sponge Theonella swinhoei. Their structures were determined by interpretation of NMR and ESIMS data. All compounds exhibited in vivo potent anti-inflammatory activity. Biological
- Festa, Carmen,De Marino, Simona,Sepe, Valentina,Monti, Maria Chiara,Luciano, Paolo,D'Auria, Maria Valeria,Débitus, Cecile,Bucci, Mariarosaria,Vellecco, Valentina,Zampella, Angela
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experimental part
p. 10424 - 10429
(2010/03/04)
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- Enzymatic synthesis of ω-carboxy-β-hydroxy-(l)-α-amino acids
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Commercially available ω-carboxy-aldehydes and glycine have been subjected to the catalytic action of an l-threonine aldolase from Escherichia coli to give the corresponding β-hydroxy-α-(l)-amino acids as a mixture of erythro/threo epimers. Specifically, the reaction with glyoxylic acid (2) gave the epimeric β-hydroxy-(l)-aspartates (t,e)-9 that could be isolated by ion-exchange chromatography in 67% yield. Following esterification and N-Boc protection, the two epimers could be isolated as pure compounds. Similarly, the aldolase-catalyzed addition of glycine to succinic semialdehyde (4) gave the expected mixture of β-hydroxy-l-α-aminoadipic acids (t)-12 and (e)-12 in 34% yield.
- Sagui, Francesca,Conti, Paola,Roda, Gabriella,Contestabile, Roberto,Riva, Sergio
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p. 5079 - 5084
(2008/09/21)
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- An efficient approach to D-threo-3-hydroxyaspartic acid for the synthesis of novel L-threo-oxazolines as selective blockers of glutamate reversed uptake
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An efficient, stereoselective synthetic strategy to D-threo-3- hydroxyaspartic acid was developed. Starting from L-(2S,3S)-N-benzoyl-3- hydroxyaspartic acid dimethyl ester by a Deoxo-fluor-catalyzed cyclization reaction, an inversion of configuration at the β-center (erythro isomer), was observed. A base-induced epimerization reaction led to the D-trans-isomer, which was hydrolyzed to give D-threo-3-hydroxyaspartic acid with excellent stereoselectivity and overall yield. Starting from D-threo-3-hydroxyaspartic acid, L-threo-oxazolines can be stereoselectively synthesized.
- De Angelis, Meri,Campiani, Giuseppe
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p. 2355 - 2357
(2007/10/03)
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- A catalyst that plays multiple roles: Asymmetric synthesis of β-substituted aspartic acid derivatives through a four-stage, one-pot procedure
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(Matrix Presented) We report a new method for the catalytic, asymmetric synthesis of β-substituted aspartic acid derivatives in which the nucleophilic catalyst serves up to four discrete roles in a one-pot procedure: catalytic dehydrohalogenation of acid chlorides to form ketenes; catalytic dehydrohalogenation of α-chloroamines to form the corresponding imines; catalyzed [2 + 2]-cycloaddition to produce intermediate acyl β-lactams; and finally, nucleophilic ring opening to afford optically enriched β-substituted aspartic acids in high enantioselectivity and diastereoselectivity.
- Dudding, Travis,Hafez, Ahmed M.,Taggi, Andrew E.,Wagerle, Ty R.,Lectka, Thomas
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p. 387 - 390
(2007/10/03)
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- Chiral salen - Aluminum complexes as catalysts for enantioselective aldol reactions of aldehydes and 5-alkoxyoxazoles: An efficient approach to the asymmetric synthesis of syn and anti β-hydroxy-α-amino acid derivatives
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Chiral aluminum complexes 3 have been employed as catalysts of the stereoselctive synthesis of cis-5-substituted 2-oxazoline-4-carboxylates from the aldol reaction of oxazole 1 and aldehydes. Cis-Product diastereoselction ranges from 3:1-50:1, while enant
- Evans, David A.,Janey, Jacob M.,Magomedov, Nabi,Tedrow, Jason S.
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p. 1884 - 1888
(2007/10/03)
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- Synthesis of 3-hydroxylated analogues of D-aspartic acid β-hydroxamate
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The two isomers (2R,3R) and (2R,3S) of 3-hydroxy-D-aspartic acid β-hydroxamate were synthesised from diethyl tartrates via the corresponding diethyl 3-hydroxyaspartates.
- Charvillon, F. Burgat,Amouroux
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p. 395 - 403
(2007/10/03)
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- 1-carboxymethoxy acetidinones and their production
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A 2-azetidinone derivative having a group of the formula STR1 wherein R1 and R2 are the same or different and each represents a hydrogen atom, alkyl, aryl or arylalkyl which may have a substituent at the 1-position and an amino group, at the 3-position, which may be acylated or protected, its salt or ester, and methods of producing the same, (1) a method comprising subjecting a 2-azetidinone derivative having a group of the formula STR2 wherein the symbols are as defined above at the 1-position and an amino group at the 3-position, its salt or ester to an acylation or protective-group introduction reaction, and (2) a method comprising reacting a 2-azetidinone derivative having a hydroxy group at the 1-position and an amino group, at the 3-position, which may be acylated or protected, or its salt with a compound of the formula STR3 wherein W is a halogen atom; other symbols are as defined above, its salt or ester. The above objective compounds are utilizable as excellent antimicrobial agents or as valuable intermediates for the synthesis of the same.
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- IMPROVED RESOLUTION OF beta -HYDROXY-DL-ASPARTIC ACID ON OPTICALLY ACTIVE RESIN CONTAINING L-LYSINE OR L-ORNITHINE. erythro
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A series of experiments on column chromatography of the optically active resin containing L-lysine or L-ornithine were carried out with pyridinium acetate and ammonium acetate solvent systems as the eluents. threo- beta -Hydroxy-DL-aspartic acid was found to be resolved on the optically active resin containing L-lysine with ammonium acetate solvent system; erythro- beta -hydroxy-DL-aspartic acid could be resolved on that containing L-ornithine with pyridinium acetate solvent system. The threo or erthro racemate was resolved on a preparative scale, and the resolution including the complete characterization of enantiomers resolved was first accomplished.
- Anpeiji,Toritani,Kawada,Kondo,Murai,Okai,Yoshida,Imai
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p. 2994 - 2998
(2007/10/02)
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