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Find video protocols related to scientific articles indexed in Pubmed.
Total Synthesis of the Macrocyclic N-Methyl Enamides Palmyrolide A and 2S-Sanctolide A.
J. Org. Chem.
PUBLISHED: 11-11-2014
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Full details of the total syntheses of the initially reported and revised structures of the neuroprotective agent palmyrolide A are reported. The key macrocyclization step was achieved using a sequential ring-closing metathesis/olefin isomerization reaction. Furthermore, the total synthesis of the related macrolide (2S)-sanctolide A is reported. The synthesis used key elements from the synthesis of palmyrolide A, including the RCM/olefin isomerization sequence. The synthetic work described herein serves to facilitate the assignment of stereochemistry of the natural product sanctolide A and demonstrates the utility of this approach for the synthesis of macrocyclic tertiary enamide natural products.
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Structure-activity relationships of the N-terminus of calcitonin gene-related peptide: key roles of alanine-5 and threonine-6 in receptor activation.
Br. J. Pharmacol.
PUBLISHED: 08-27-2014
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The N-terminus of calcitonin gene-related peptide (CGRP) is important for receptor activation, especially the disulphide-bonded ring (residues 1-7). However, the roles of individual amino acids within this region have not been examined and so the molecular determinants of agonism are unknown. This study has examined the role of residues 1, 3-6 and 8-9, excluding Cys-2 and Cys-7.
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Synthesis and evaluation of 9-deoxy analogues of (-)-thysanone, an inhibitor of HRV 3C protease.
Eur J Med Chem
PUBLISHED: 08-26-2014
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9-Deoxy analogues of the HRV 3C protease inhibitor (-)-thysanone display better inhibitory properties than the natural product, inferring the C9-OH hinders binding to the enzyme.
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Recent developments in transition metal-catalysed spiroketalisation.
Org. Biomol. Chem.
PUBLISHED: 08-20-2014
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The spiroketal motif occurs in a wide range of biologically active natural products and represents a valuable target in medicinal chemistry and total synthesis. In recent years, innovative new synthetic methods have substantially expanded the range of potential precursors, cyclisation modes and opportunities for asymmetric catalysis and tandem processes. This Perspective aims to highlight recent rapid advances in the use of transition metal catalysis for spiroketal formation, in the context of our own investigations into gold-catalysed asymmetric spiroketalisation.
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Toward an asymmetric synthesis of the dimeric pyranonaphthoquinone antibiotic crisamicin A.
J. Org. Chem.
PUBLISHED: 07-23-2014
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A full account of our efforts toward an asymmetric synthesis of crisamicin A are presented. The key steps include a Hauser-Kraus annulation of a cyanophthalide with a chiral enone-lactone, a stereoselective cyclization-reduction to install the pyran unit, and a Suzuki homocoupling to forge the key biaryl bond. This work has culminated in the asymmetric synthesis of a dimer bearing the complete carbon skeleton of the dimeric pyranonaphthoquinone natural product crisamicin A.
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Convergent chemoenzymatic synthesis of a library of glycosylated analogues of pramlintide: structure-activity relationships for amylin receptor agonism.
Org. Biomol. Chem.
PUBLISHED: 07-17-2014
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Pramlintide (Symlin®), a synthetic analogue of the naturally occurring pancreatic hormone amylin, is currently used with insulin in adjunctive therapy for type 1 and type 2 diabetes mellitus. Herein we report a systematic study into the effect that N-glycosylation of pramlintide has on activation of amylin receptors. A highly efficient convergent synthetic route, involving a combination of solid phase peptide synthesis and enzymatic glycosylation, delivered a library of N-glycosylated variants of pramlintide bearing either GlcNAc, the core N-glycan pentasaccharide [Man3(GlcNAc)2] or a complex biantennary glycan [(NeuAcGalGlcNAcMan)2Man(GlcNAc)2] at each of its six asparagine residues. The majority of glycosylated versions of pramlintide were potent receptor agonists, suggesting that N-glycosylation may be used as a tool to optimise the pharmacokinetic properties of pramlintide and so deliver improved therapeutic agents for the treatment of diabetes and obesity.
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Protecting-group-free one-pot synthesis of glycoconjugates directly from reducing sugars.
Angew. Chem. Int. Ed. Engl.
PUBLISHED: 07-02-2014
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The conversion of sugars into glycomimetics typically involves multiple protecting-group manipulations. The development of methodology allowing the direct aqueous conversion of free sugars into glycosides, and mimics of oligosaccharides and glycoconjugates in a high-yielding and stereoselective process is highly desirable. The combined use of 2-azido-1,3-dimethylimidazolinium hexafluorophosphate and the Cu-catalyzed Huisgen cycloaddition allowed the synthesis of a range of glycoconjugates in a one-step reaction directly from reducing sugars under aqueous conditions. The reaction, which is completely stereoselective, may be applied to the convergent synthesis of triazole-linked glycosides, oligosaccharides, and glycopeptides. The procedure provides a method for the one-pot aqueous ligation of oligosaccharides and peptides bearing alkyne side chains.
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Total synthesis of virgatolide B via exploitation of intramolecular hydrogen bonding.
J. Org. Chem.
PUBLISHED: 05-23-2014
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A full account of the enantioselective total synthesis of virgatolide B is reported. Key features of the synthesis include an sp(3)-sp(2) Suzuki-Miyaura cross-coupling of a ?-trifluoroboratoamide with an aryl bromide, regioselective intramolecular carboalkoxylation, and a 1,3-anti-selective Mukaiyama aldol reaction. Intramolecular hydrogen bonding governed the regioselectivity of the key spiroketalization step, affording the natural product as a single regioisomer.
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Synthesis of truncated analogues of preptin-(1–16), and investigation of their ability to stimulate osteoblast proliferation.
Bioorg. Med. Chem.
PUBLISHED: 03-05-2014
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Preptin, a 34-amino acid residue peptide hormone is co-secreted with insulin from the ?-pancreatic cells and is active in fuel metabolism. We have previously established that a shorter fragment of preptin, namely preptin-(1–16), stimulates bone growth by proliferation and increasing the survival rate of osteoblasts. This was demonstrated in both in vitro and in vivo models. These findings suggest that preptin-(1–16) could play an important role in the anabolic therapy of osteoporosis. However, due to the large size of the peptide it is not an ideal therapeutic agent. The aim of this study was to identify the shortest preptin analogue that retains or even increases the bone anabolic activity as compared to the parent preptin-(1–16) peptide. Truncations were made in a methodical manner from both the N-terminus and the C-terminus of the peptide, and the effect of these deletions on the resulting biological activity was assessed. In order to improve the enzymatic stability of the shortest yet active analogue identified, ruthenium-catalysed ring closing metathesis was used to generate a macrocyclic peptide using allylglycine residues as handles for ring formation. We have successfully identified a short 8-amino acid preptin (1–8) fragment that retains an anabolic effect on the proliferation of primary rat osteoblasts and enhances bone nodule formation. Preptin (1–8) is a useful lead compound for the development of orally active therapeutics for the treatment of osteoporosis.
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Synthesis and methemoglobinemia-inducing properties of benzocaine isosteres designed as humane rodenticides.
Bioorg. Med. Chem.
PUBLISHED: 02-03-2014
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A number of isosteres (oxadiazoles, thiadiazoles, tetrazoles and diazines) of benzocaine were prepared and evaluated for their capacity to induce methemoglobinemia-with a view to their possible application as humane pest control agents. It was found that an optimal lipophilicity for the formation of methemoglobin (metHb) in vitro existed within each series, with 1,2,4-oxadiazole 3 (metHb%=61.0±3.6) and 1,3,4-oxadiazole 10 (metHb%=52.4±0.9) demonstrating the greatest activity. Of the 5 candidates (compounds 3, 10, 11, 13 and 23) evaluated in vivo, failure to induce a lethal end-point at doses of 120mg/kg was observed in all cases. Inadequate metabolic stability, particularly towards hepatic enzymes such as the CYPs, was postulated as one reason for their failure.
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Preparation of truncated orf virus entry fusion complex proteins by chemical synthesis.
J. Pept. Sci.
PUBLISHED: 01-27-2014
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Members of the Chordopoxvirinae subfamily possess an unusual 11 protein entry-fusion complex (EFC) that is highly conserved and present in all species. The mode of action of this EFC is unknown, and the interactions of the constituent proteins are uncharacterised. Here, we present the chemical synthesis of membrane domain truncated linear constructs of two EFC proteins in orf virus, ORFV036 and 049. By using Boc solid phase peptide synthesis and native chemical ligation methods, these truncated proteins have been readily prepared in milligram quantities. These robust synthetic protocols allow ready access to these polypeptides to facilitate biological studies.
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An investigation of the role of the adiponectin variable domain on the stability of the collagen-like domain.
Biopolymers
PUBLISHED: 01-24-2014
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The chemical synthesis is described of a polypeptide construct possessing both the variable and the collagen-like domain of adiponectin, which can be used as a model system for probing the influence of the variable domain on multimerization of this important circulating hormone. Using a collagen domain repeat peptide unit derived from native adiponectin or a glutamic acid analogue was ineffective due to noncollagenous conformational properties in both cases. However, employing a collagen model peptide and linking this to the variable domain thioester peptide using native chemical ligation proved effective. The 63 residue peptide was characterized by circular dichroism and mass spectrometry which demonstrated that a collagen-like triple-helical structure was preserved. © 2014 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 102: 313-321, 2014.
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Plant antimicrobial peptides snakin-1 and snakin-2: chemical synthesis and insights into the disulfide connectivity.
Chemistry
PUBLISHED: 01-19-2014
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Antimicrobial peptides and proteins represent an important class of plant defensive compounds against pathogens and provide a rich source of lead compounds in the field of drug discovery. We describe the effective preparation of the cysteine-rich snakin-1 and -2 antimicrobial peptides by using a combination of solid-phase synthesis and native chemical ligation. A subsequent cysteine/cystine mediated oxidative folding to form the six internal disulfide bonds concurrently gave the folded proteins in 40-50?% yield. By comparative evaluation of mass spectrometry, HPLC, biological data and trypsin digest mapping of folded synthetic snakin-2 compared to natural snakin-2, we demonstrated that synthetic snakin-2 possesses full antifungal activity and displayed similar chromatographic behaviour to natural snakin-2. Trypsin digest analysis allowed tentative assignment of three of the purported six disulfide bonds.
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Glucose as an agent of post-translational modification in diabetes - New cardiac epigenetic insights.
Life Sci.
PUBLISHED: 01-16-2014
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Diabetes elicits cardiac metabolic stress involving impaired glucose uptake and metabolic substrate shifts. Diabetic cardiac pathology is well documented in human patients and experimental animal models to be characterized by diastolic dysfunction, but the underlying mechanisms are not well understood. Signaling disturbances involved in cardiac insulin resistance are linked to glucose handling abnormalities. Both reversible (e.g. O-GlcNAc) and irreversible (e.g. AGEs) glucose-modifications of cardiomyocyte extracellular and intracellular proteins are implicated in structural and functional alterations underlying pathology in the diabetic heart. This review highlights some aspects of the epigenetic roles played by glucose (and related hexose sugars) in mediating diabetic cardiac pathology with specific consideration for the mechanisms impinging on post-translational modifications which have key signaling and mechanical impacts.
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Structure and activity of Streptococcus pyogenes SipA: a signal peptidase-like protein essential for pilus polymerisation.
PLoS ONE
PUBLISHED: 01-01-2014
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The pili expressed on the surface of the human pathogen Streptococcus pyogenes play an important role in host cell attachment, colonisation and pathogenesis. These pili are built from two or three components, an adhesin subunit at the tip, a major pilin that forms a polymeric shaft, and a basal pilin that is attached to the cell wall. Assembly is carried out by specific sortase (cysteine transpeptidase) enzyme. These components are encoded in a small gene cluster within the S. pyogenes genome, often together with another protein, SipA, whose function is unknown. We show through functional assays, carried out by expressing the S. pyogenes pilus components in Lactococcus lactis, SipA from the clinically important M1T1 strain is essential for pilus assembly, and that SipA function is likely to be conserved in all S. pyogenes. From the crystal structure of SipA we confirm that SipA belongs to the family of bacterial signal peptidases (SPases), which process the signal-peptides of secreted proteins. In contrast to a previous arm-swapped SipA dimer, this present structure shows that its principal domain closely resembles the catalytic domain of SPases and has a very similar peptide-binding cleft, but it lacks the catalytic Ser and Lys residues characteristic of SPases. In SipA these are replaced by Asp and Gly residues, which play no part in activity. We propose that SipA functions by binding a key component at the bacterial cell surface, in a conformation that facilitates pilus assembly.
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Total Synthesis of Heronapyrrole C.
Org. Lett.
PUBLISHED: 12-18-2013
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A flexible total synthesis of the 2-nitropyrrole-derived marine natural product, (+)-heronapyrrole C, is reported. The approach is based on regioselective access to key building blocks containing the rare 4-substituted 2-nitropyrrole motif. Sharpless asymmetric epoxidation and dihydroxylation and a Shi epoxidation were used to introduce the five stereogenic centers of the bis-THF-diol side chain. The N-benzoyloxymethyl (Boz) protecting group was crucial for functionalization of the 2-nitropyrrole moiety and enabling final deprotection under mild conditions.
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Synthesis of an Azido Precursor to (2S,5R)-5-Hydroxylysine Using an Asymmetric Organocatalytic Chlorination/Reduction Sequence.
J. Org. Chem.
PUBLISHED: 11-08-2013
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An efficient, robust, and scalable synthesis of an azido precursor to the modified amino acid (2S,5R)-5-hydroxylysine was developed on the basis of the use of a highly stereoselective organocatalytic ?-chlorination-reduction protocol. The final Fmoc-protected (2S,5R)-6-azido-5-hydroxylysine derivative can be used in solid-phase peptide synthesis, providing access to proteins that contain large quantities of post-translationally modified lysine (e.g., collagens).
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Synthesis and methemoglobinemia-inducing properties of analogues of para-aminopropiophenone designed as humane rodenticides.
Bioorg. Med. Chem. Lett.
PUBLISHED: 08-30-2013
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A number of structural analogues of the known toxicant para-aminopropiophenone (PAPP) have been prepared and evaluated for their capacity to induce methemoglobinemia-with a view to their possible application as humane pest control agents. It was found that an optimal lipophilicity for the formation of methemoglobin (metHb) in vitro existed for alkyl analogues of PAPP (aminophenones 1-20; compound 6 metHb%=74.1±2). Besides lipophilicity, this structural sub-class suggested there were certain structural requirements for activity, with both branched (10-16) and cyclic (17-20) alkyl analogues exhibiting inferior in vitro metHb induction. Of the four candidates (compounds 4, 6, 13 and 23) evaluated in vivo, 4 exhibited the greatest toxicity. In parallel, aminophenone bioisosteres, including oximes 30-32, sulfoxide 33, sulfone 34 and sulfonamides 35-36, were found to be inferior metHb inducers to lead ketone 4. Closer examination of Hammett substituent constants suggests that a particular combination of the field and resonance parameters may be significant with respect to the redox mechanisms behind PAPPs metHb toxicity.
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Total synthesis of virgatolide B.
Org. Lett.
PUBLISHED: 08-19-2013
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The first total synthesis of the benzannulated spiroketal virgatolide A is presented. Key features include sp(3)-sp(2) Suzuki coupling of an enantiomerically enriched ?-trifluoroboratoamide and an aryl bromide, regioselective intramolecular carboalkoxylation, and a 1,3-anti-selective Mukaiyama aldol reaction followed by global deprotection/cyclization with regioselectivity governed by internal hydrogen bonding.
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Novel preparation of chiral ?-amino acids using the Mitsunobu-Tsunoda reaction.
Chem. Commun. (Camb.)
PUBLISHED: 07-24-2013
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An efficient synthesis of racemic or optically active ?-amino acids by modified-Mitsunobu alkylation of a racemic or chiral glycine template from alcohols was developed. Libraries of amino acids were prepared in moderate to good yield with good to high enantioselectivity. This simple method widens the scope for preparation of structurally diverse amino acids.
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Enantioselective access to benzannulated spiroketals using a chiral sulfoxide auxiliary.
Org. Biomol. Chem.
PUBLISHED: 07-02-2013
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This article describes our efforts to develop an asymmetric synthesis of bisbenzannulated spiroketals using a chiral sulfoxide auxiliary. Our primary focus was on the synthesis of the 3H-spiro[benzofuran-2,2-chroman] ring system, the spirocyclic core of the rubromycin family. Our strategy employed the use of lithium-halogen exchange on a racemic bromospiroketal in order to attach a chiral sulfoxide, thus producing two diastereomers. The diastereomers were separable, enabling isolation of each spiroketal enantiomer. Subsequent cleavage of the sulfoxide group from each diastereomer yielded the respective parent spiroketal in high enantiopurity.
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Direct peptide lipidation through thiol-ene coupling enables rapid synthesis and evaluation of self-adjuvanting vaccine candidates.
Angew. Chem. Int. Ed. Engl.
PUBLISHED: 06-30-2013
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A radical lipidation: Application of a novel thiol-ene lipidation enables the one-step synthesis of self-adjuvanting antigenic peptides as vaccine candidates. The resultant monoacyl lipopeptides are shown to activate monocytes in a robust manner.
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Chemical synthesis of a masked analogue of the fish antifreeze potentiating protein (AFPP).
Org. Biomol. Chem.
PUBLISHED: 06-21-2013
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A recently identified Antarctic fish protein termed antifreeze potentiating protein (AFPP) is thought to act as an adjunct to the previously characterised antifreeze glycoproteins (AFGPs), the two acting together to inhibit ice crystal growth in vivo. Elucidating the functional properties of the new AFPP requires access to large amounts of pure product, but the paucity of natural material necessitates alternative approaches. We therefore embarked on the total chemical synthesis of the AFPP, through a convergent ligation strategy. After many challenges, mostly due to the solubility issues of the peptide fragments, and several revisions of the original synthetic strategy, we have successfully synthesized a masked analogue of AFPP. The key to the successful synthesis was the use of a solubilising tag attached through a hydrolysable linker.
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An important side reaction using the thiol, 3,6-dioxa-1,8-octanedithiol (DODT), in 9-fluorenylmethoxycarbonyl-based solid phase peptide synthesis.
J. Pept. Sci.
PUBLISHED: 06-03-2013
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A considerable quantity of an alkylation by-product is observed when using 3,6-dioxa-1,8-octanedithiol as a scavenger during acidic release of peptides containing the thioether amino acid methionine from the solid support. Adjustment of the cleavage conditions by replacement of 3,6-dioxa-1,8-octanedithiol with ethane dithiol or by using methionine sulfoxide as an alternative to methionine resulted in no such impurity. The by-product was detectable by liquid chromatography and mass spectrometry and characterised by NMR spectroscopy of an isolated model peptide. It could be effectively removed in a separate post cleavage step by treatment with dilute aqueous acid at 37?°C. Copyright © 2013 European Peptide Society and John Wiley & Sons, Ltd.
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Prodrugs of N-dicarboximide derivatives of the rat selective toxicant norbormide.
Bioorg. Med. Chem.
PUBLISHED: 05-10-2013
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Norbormide [5-(?-hydroxy-?-2-pyridylbenzyl)-7-(?-2-pyridylbenzylidene)-5-norbornene-2,3-dicarboximide] (NRB), an existing but infrequently used rodenticide, is known to be uniquely toxic to rats but relatively harmless to other rodents and mammals. However, one major drawback of NRB as a viable rodenticide relates to an evolutionary aversion developed by the rat leading to sub-lethal dosing due to either its unpleasant taste or rapid onset of effects. A series of NRB-derived prodrugs were prepared in an effort to mask this acute response. Their synthesis and biological evaluation (in vitro vasoconstrictory activity, in vitro hydrolytic and enzymatic stability and lethality/palatability in vivo) is described. Prodrug 2 displayed the most promising profile with respect to a delay in the onset of symptoms and was subsequently demonstrated to be significantly more palatable to rats. Moreover, prodrug 25 was found to be largely accepted by rats in a choice trial, resulting in high mortality.
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One-pot synthesis of water soluble iron nanoparticles using rationally-designed peptides and ligand release.
Chem. Commun. (Camb.)
PUBLISHED: 04-11-2013
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Herein we report the rational design of new phosphopeptides for control of nucleation, growth and aggregation of water-soluble, superparamagnetic iron-iron oxide core-shell nanoparticles. The use of the designed peptides enables a one-pot synthesis that avoids utilizing unstable or toxic iron precursors, organic solvents, and the need for exchange of capping agent after synthesis of the NPs.
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Synthesis of the griseusin B framework via a one-pot annulation-methylation-double deprotection-spirocyclization sequence.
Org. Lett.
PUBLISHED: 04-05-2013
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A highly convergent synthesis of the griseusin B scaffold is described. The key step involves an efficient one-pot Hauser-Kraus annulation-methylation-double deprotection-spirocyclization sequence that directly affords the target parent tetracyclic ring system.
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Synthesis of the IGF-II-like hormone vesiculin using regioselective formation of disulfide bonds.
Org. Biomol. Chem.
PUBLISHED: 03-28-2013
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Diabetes mellitus, characterised by hyperglycemia and altered ?-cell function, is an increasingly common disorder affecting millions of individuals world-wide. While therapeutic regimens exist to manage the condition, diabetic individuals remain prone to complications that are detrimental to both their length and quality of life. An improved understanding of the disease which may then enable development of new treatments is therefore a desirable goal. Vesiculin, a novel IGF-II-like protein was recently isolated from the secretory granules of murine ?-cells, and preliminary studies indicate it is capable of signalling via the insulin receptor (IR)/insulin-like growth factor receptor 1(IGF1R) family giving it the potential to elicit both metabolic and mitogenic responses in the beta-cell. In order to facilitate further studies on this new member of the insulin-family of hormones, we undertook a chemical synthesis of the protein using regioselective disulfide bond formation.
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Structure and dynamics of human Nedd4-1 WW3 in complex with the ?ENaC PY motif.
Biochim. Biophys. Acta
PUBLISHED: 03-04-2013
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Nedd4-1 (neuronal precursor cell expressed developmentally downregulated gene 4-1) is an E3 ubiquitin ligase that interacts with and negatively regulates the epithelial Na(+) channel (ENaC). The WW domains of Nedd4-1 bind to the ENaC subunits via recognition of PY motifs. Human Nedd4-1 (hNedd4-1) contains four WW domains with the third domain (WW3*) showing the strongest affinity to the PY motif. To understand the mechanism underlying this binding affinity, we have carried out NMR structural and dynamics analyses of the hNedd4-1 WW3* domain in complex with a peptide comprising the C-terminal tail of the human ENaC ?-subunit. The structure reveals that the peptide interacts in a similar manner to other WW domain-ENaC peptide structures. Crucial interactions that likely provide binding affinity are the broad XP groove facilitating additional contacts between the WW3* domain and the peptide, compared to similar complexes, and the large surface area buried (83?(2)) between R430 (WW3*) and L647 (?ENaC). This corroborates the model-free analysis of the (15)N backbone relaxation data, which showed that R430 is the most rigid residue in the domain (S(2)=0.90±0.01). Carr-Purcell-Meiboom-Gill relaxation dispersion analysis identified two different conformational exchange processes on the ?s-ms time-scale. One of these processes involves residues located at the peptide binding interface, suggesting conformational exchange may play a role in peptide recognition. Thus, both structural and dynamic features of the complex appear to define the high binding affinity. The results should aid interpretation of biochemical data and modeling interfaces between Nedd4-1 and other interacting proteins.
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Synthesis of stable isotope-labelled monolysyl advanced glycation endproducts.
Amino Acids
PUBLISHED: 03-04-2013
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Advanced Glycation Endproducts (AGEs) are modified amino acids that form on proteins and are known to be implicated in the pathogenesis of diabetes and related diseases. Ready access to synthetic stable isotope-labelled AGEs allows for quantitative mass spectrometry studies to be undertaken, providing key insights into the roles AGEs play in the progression of such diseases. However, the majority of current syntheses of these compounds suffer from poor yields and lengthy procedures and are not suitable for the purposes required here. Here, we report robust syntheses of stable isotope-labelled monolysyl AGEs, N(?)-(carboxymethyl)lysine, N(?)-(carboxyethyl)lysine and pyrraline, that provide straightforward access to these compounds for quantitative amino acid analysis. This work will facilitate future investigations with these compounds and lead to a better understanding of the roles they play in diabetes and related diseases.
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Synthesis of a 6,6-spiroketal amino acid and its incorporation into a peptide turn sequence using solid-phase peptide synthesis.
Chemistry
PUBLISHED: 02-19-2013
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Spiropins for SPPS: The rigid structure of an anomerically stabilised spiroketal motif enables the appendage of substituents in a fixed conformation. To assess the ability of a spiroketal motif to induce a turn structure and participate in solid-phase peptide synthesis (SPPS), an Fmoc-spiroketal amino acid was synthesised and incorporated into a spiroketal-containing cyclic peptide.
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A comparison of Boc and Fmoc SPPS strategies for the preparation of C-terminal peptide ?-thiolesters: NY-ESO-1 (39) Cys-(68) Ala-COSR.
Biopolymers
PUBLISHED: 02-06-2013
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The synthesis of a polypeptide derived from the cancer testis antigen NY-ESO-1 bearing a C-terminal ?-thiolester is described. Employing tert-butyloxycarbonyl solid phase peptide synthesis the thiolester moiety was installed on-resin using a mercaptopropionic acid linker, thereby requiring no post synthetic manipulations and delivering the requisite ?-thiolester polypeptide after cleavage from the resin with HF. Several 9-fluorenylmethyloxycarbonyl solid phase peptide synthesis approaches whereby the thiolester was required to be introduced in a post synthesis manner were examined concurrently. These comprised syntheses on two different "safety catch" linkers, an N-alkyl-N-acyl sulphonamide and an N-acyl benzimidazolone wherein the thiolester is generated from an activated precursor. The condensation of a mercaptan with the C-terminal carboxylate in a direct thiolesterification reaction was also examined. When using either of the three 9-fluorenylmethyloxycarbonyl-based approaches, the linear polypeptide could be assembled straightforwardly on the solid phase resin; however, a thiolesterification of the C-terminal carboxyl of the fully side chain protected peptide proved to be the most effective post-assembly method for the installation of the C-terminal thiolester. © 2013 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 100: 356-365, 2013.
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Total synthesis of chaetoquadrins A-C.
Org. Lett.
PUBLISHED: 01-17-2013
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The first total synthesis of the monoamine oxidase inhibitors chaetoquadrins A-C has been accomplished. Key steps in the synthesis include an aromatic Claisen rearrangement, asymmetric boron aldol reaction and acid-mediated spiroketalization. Comparison of spectral data for the synthetic spiroketals confirmed the proposed structure for these natural products.
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Formal synthesis of berkelic acid: a lesson in ?-alkylation chemistry.
J. Org. Chem.
PUBLISHED: 11-28-2011
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The full details of our enantioselective formal synthesis of the biologically active natural product berkelic acid are described. The insertion of the C-18 methyl group proved challenging, with three different approaches investigated to install the correct stereochemistry. Our initial Horner-Wadsworth-Emmons/oxa-Michael approach to the berkelic acid core proved unsuccessful upon translation to the natural product itself. However, addition of a silyl enol ether to an oxonium ion, followed by a one-pot debenzylation/spiroketalisation/thermodynamic equilibration procedure, afforded the tetracyclic structure of the berkelic acid core as a single diastereoisomer.
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Synthesis of the bis-spiroacetal core of the antimitotic agent spirastrellolide B.
J. Org. Chem.
PUBLISHED: 10-20-2011
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The spirastrellolides are a family of potent antimitotic agents isolated from the marine sponge Spirastrella coccinea . Synthetic studies toward the DEF bis-spiroacetal core of spirastrellolide B are reported. A modular approach was pursued by the use of two dithiane disconnections to enable a highly convergent synthesis. The ease of lithiation and nucleophilicity of these 2-substituted-1,3-dithianes were investigated during the course of the synthesis, and the alkylations were found to proceed most efficiently at elevated temperatures. Formation of the [5,6,6]-bis-spiroacetal ring system was achieved via a double dithiane deprotection/spiroacetalization strategy.
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Synthesis of an NDPK phosphocarrier domain peptide containing a novel triazolylalanine analogue of phosphohistidine using click chemistry.
Org. Lett.
PUBLISHED: 09-22-2011
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Click phosphorylation of a propargylated unprotected peptide and phosphoryl azide using chaotrope-assisted Cu(I)-catalyzed 1,3-dipolar cycloaddition enabled a high-yielding and rapid synthesis of a nucleoside diphosphate kinase (NDPK) phosphocarrier domain. The synthesis showcases a valuable synthetic platform for the synthesis of biologically relevant phosphopeptide analogues.
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An enantioselective formal synthesis of berkelic acid.
Org. Lett.
PUBLISHED: 09-14-2011
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An enantioselective formal synthesis of berkelic acid is described. The key step involves a late-stage silyl enol ether addition to a benzannulated oxonium ion with subsequent spiroketalization leading to construction of the tetracyclic core. Thermodynamically controlled equilibration under acidic conditions affords the desired spiroketal configuration as a single diastereoisomer.
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The synthesis of dehydrotryptophan and dehydrotryptophan-containing peptides.
Org. Biomol. Chem.
PUBLISHED: 07-08-2011
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Dehydrotryptophan and its derivatives are non-proteinogenic amino acids commonly found in peptide-based natural products produced by microorganisms, marine organisms and plants. These non-proteinogenic amino acids are found in secondary metabolites and are formed by post translational modification processes. Although comprehensive reviews on the synthesis of dehydroamino acids are available, this perspective focuses solely on methods to synthesise the dehydrotryptophan-containing segment of naturally occurring peptides, amino acids and their derivatives.
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The translocator protein (peripheral benzodiazepine receptor) mediates rat-selective activation of the mitochondrial permeability transition by norbormide.
Biochim. Biophys. Acta
PUBLISHED: 06-14-2011
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We have investigated the mechanism of rat-selective induction of the mitochondrial permeability transition (PT) by norbormide (NRB). We show that the inducing effect of NRB on the PT (i) is inhibited by the selective ligands of the 18kDa outer membrane (OMM) translocator protein (TSPO, formerly peripheral benzodiazepine receptor) protoporphyrin IX, N,N-dihexyl-2-(4-fluorophenyl)indole-3-acetamide and 7-chloro-5-(4-chlorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one; and (ii) is lost in digitonin mitoplasts, which lack an intact OMM. In mitoplasts the PT can still be induced by the NRB cationic derivative OL14, which contrary to NRB is also effective in intact mitochondria from mouse and guinea pig. We conclude that selective NRB transport into rat mitochondria occurs via TSPO in the OMM, which allows its translocation to PT-regulating sites in the inner membrane. Thus, species-specificity of NRB toward the rat PT depends on subtle differences in the structure of TSPO or of TSPO-associated proteins affecting its substrate specificity.
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Enantioselective synthesis of pyranonaphthoquinone antibiotics using a CBS reduction/cross-metathesis/oxa-Michael strategy.
Org. Biomol. Chem.
PUBLISHED: 06-08-2011
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The enantioselective syntheses of deoxydihydrokalafungin (5), cis-deoxydihydrokalafungin (6) and deoxykalafungin (7) are reported. The strategy was based on 4 key reactions: (1) CBS reduction of prochiral ketone 10 to introduce chirality at C-1, (2) radical allylation of quinone 9a, (3) cross-metathesis of dimethoxynaphthalene 13 with methyl acrylate, and (4) intramolecular oxa-Michael addition of alcohol 8 to form the core naphthopyran ring system. This novel approach delivers naphthopyrans possessing the natural trans-stereochemistry observed in the pyranonaphthoquinone family of antibiotics.
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Synthesis of MUC1 Neoglycopeptides using efficient microwave-enhanced chaotrope-assisted click chemistry.
Org. Biomol. Chem.
PUBLISHED: 01-20-2011
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The first synthesis of click neoglycopeptide analogues of the biologically relevant MUC1 sequence is reported. In the process, microwave-enhanced chaotrope-assisted click reaction conditions that may be used on a routine basis for the synthesis of click peptide conjugates have been developed. The convergent route for the synthesis of neoglycopeptides using these reaction conditions enables the facile, rapid, and highly efficient preparation of focused neoglycopeptide libraries of defined chemical structure for biological evaluation.
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Synthesis of methyl N-Boc-(2S,4R)-4-methylpipecolate.
J. Org. Chem.
PUBLISHED: 11-23-2010
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An efficient stereoselective synthesis of fully protected (2S,4R)-4-methylpipecolic acid has been developed. The synthesis was achieved by initial asymmetric ?-alkylation of glycine with a chiral iodide, affording the linear precursor as a single stereoisomer. Subsequent aldehyde formation using OsO(4)/NaIO(4) followed by immediate intramolecular cyclization afforded an enamine that was then subjected to hydrogenation to give the final compound in 23% yield over 10 steps.
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Synthesis of a functionalized 7,6-bicyclic spiroimine ring fragment of the spirolides.
Org. Lett.
PUBLISHED: 10-28-2010
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The asymmetric synthesis of a functionalized 7,6-spiroimine related to the spirolides is described. Intermolecular Diels-Alder cycloaddition of a chiral trisubstituted dienophile and Danishefskys diene enabled simultaneous installation of the C7 and C29 stereocenters. Further transformations and late-stage aza-Wittig cyclization afforded the spiroimine in good yield. During this study, an unprecedented 14-membered dialdimine was also obtained.
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Synthesis and assignment of stereochemistry of the antibacterial cyclic peptide xenematide.
Org. Biomol. Chem.
PUBLISHED: 10-15-2010
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The synthesis of the antimicrobial cyclic peptide xenematide was accomplished by Fmoc solid phase peptide synthesis and the key esterification reaction was achieved using a modified Yamaguchi esterification. Comparison of the optical rotation and NMR data of the synthesized diastereomers to that of the natural product confirmed the structure of xenematide to be PA-L-[Thr-L-Trp-D-Trp-?-Ala]. (PA = phenylacetyl).
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Heteroatom-directed reverse Wacker oxidations. Synthesis of the reported structure of (-)-herbaric acid.
J. Org. Chem.
PUBLISHED: 09-30-2010
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A microwave-assisted chemoenzymatic resolution has been used to install the C3 stereocenter of the reported structure of the fungal metabolite herbaric acid in high enantiomeric excess. The synthesis and stereochemical assignment was accomplished using a completely regioselective anti-Markovnikov addition of water to vinylphthalide 3, achieved using a heteroatom-directed Wacker oxidation that proceeds with retention of stereochemistry. These results establish that so-called "reverse" Wacker oxidations are a viable alternative to hydroboration/oxidation procedures.
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Toward the total chemical synthesis of the cancer protein NY-ESO-1.
Biopolymers
PUBLISHED: 07-02-2010
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During the course of developing a synthetic route for the cancer protein NY-ESO-1 using native chemical ligation, a number of the required thioester polypeptide fragments were unable to be synthesized effectively using Boc solid phase peptide synthesis. Modification of the SPPS protocols to include an arginine tag at the C terminus linked via the thioester resulted in a better purity profile and enhanced solubility, facilitating purification by HPLC. During preparation of another reactive partner for ligation that contained an internal Cys(Acm) residue by Fmoc SPPS, extensive loss of the Acm group occurred during cleavage from the resin while substitution with Cys(tBu) resulted in no loss of protecting group. It was shown that native chemical ligation of N-terminal cysteine peptide 155-180 containing the Cys(tBu) residue with thioester 140-154 was slow, incomplete and led to extensive HPLC column fouling. Subsequent incorporation of a C-terminal arginine tag into the N-terminal NY-ESO-1 155-180 fragment joined by a base labile 4-hydroxymethylbenzoic acid (HMBA) linker facilitated rapid quantitative ligation. The HMBA linker was demonstrated to be stable to the conditions required for native chemical ligation, subsequent transformations and final purification. Importantly it was effectively removed at pH=10.
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Synthesis of the bis-spiroacetal C25-C40 moiety of the antimitotic agent spirastrellolide B using a bis-dithiane deprotection/spiroacetalisation sequence.
Chem. Commun. (Camb.)
PUBLISHED: 05-05-2010
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Use of a bis-dithiane deprotection-tandem bis-spiroacetalisation sequence was key to the successful synthesis of the [5,6,6]-bis-spiroacetal of the antimitotic agent spirastrellolide B, achieved in a highly convergent fashion involving successive dithiane alkylations.
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A flexible asymmetric synthesis of the tetracyclic core of berkelic acid using a Horner-Wadsworth-Emmons/oxa-Michael cascade.
Org. Biomol. Chem.
PUBLISHED: 01-26-2010
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The one-pot Horner-Wadsworth-Emmons/oxa-Michael cascade followed by spiroketalisation affords the tetracyclic benzannulated spiroketal core of berkelic acid, an extremophile natural product with selective activity against ovarian cancer.
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A one-pot approach to neoglycopeptides using orthogonal native chemical ligation and click chemistry.
Org. Lett.
PUBLISHED: 10-22-2009
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The powerful combination of native chemical ligation and click chemistry has been used to affect a one-pot synthesis of neoglycopeptides from propargyl-containing peptides using GalNAc-N(3) as the glycan component. A versatile chemical toolkit for the fully convergent synthesis of neoglycoproteins using click chemistry, native chemical ligation, and kinetically controlled ligation is thus demonstrated.
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Synthesis and reactivity of beta-methoxymethyl enecarbamates.
J. Org. Chem.
PUBLISHED: 10-20-2009
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Beta-methoxymethyl enecarbamates (e.g., 1) have been prepared in a single step from alpha-methoxy carbamates. In the presence of a mild Lewis acid, compound 1 underwent substitution with a variety of nucleophiles including indoles, electron-rich aromatics, silyl enol ethers, and 2-trimethylsilyloxyfuran.
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Synthesis of natural products containing spiroketals via intramolecular hydrogen abstraction.
Org. Biomol. Chem.
PUBLISHED: 10-07-2009
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Although known for over a quarter of a century, the oxidative radical cyclisation route to spiroketals has found limited use in natural product synthesis in comparison to classical approaches. Its successful application in this field of research forms the subject of this perspective.
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Pyranonaphthoquinone derivatives of eleutherin, ventiloquinone L, thysanone and nanaomycin A possessing a diverse topoisomerase II inhibition and cytotoxicity spectrum.
Bioorg. Med. Chem.
PUBLISHED: 07-22-2009
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A series of pyranonaphthoquinone derivatives related to the known topoisomerase II inhibitor eleutherin 1 have been shown to act as specific topoisomerase II catalytic inhibitors, with several analogues displaying greater potency than the natural product itself. Amongst the compounds tested were the natural products ventiloquinone L 4 and thysanone 8 with a diverse range of topoisomerase II inhibition properties being observed. Interestingly, the natural products are generally weaker inhibitors than their synthetic counterparts, emphasising that subtle changes in the basic molecular structure of a natural product led to significant changes in the inhibition profile. It has also been demonstrated for the first time that analogues related to nanaomycin A and cardinalin-type dimeric pyranonaphthoquinones exhibit potent topoisomerase II inhibitory properties. With respect to structural features, it appears that the nature of the substituents at C1 on the pyran ring and oxygenated substituents on the aryl ring are critical for anti-topoII activity. Importantly, the topoisomerase II inhibition strength does not correlate well with the measured cytotoxicity against yeast, indicating that other molecular features in the pyranonaphthoquinone family must be considered for the design and use of this structural class as highly specific topoisomerase II inhibitors.
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Synthesis of fish antifreeze neoglycopeptides using microwave-assisted "click chemistry".
Org. Lett.
PUBLISHED: 05-29-2009
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Microwave-enhanced click glycoconjugation of a propargylated alpha-GalNAc sugar moiety with an azido-functionalized amino acid or multiazido-functionalized peptides using a catalytic quantity of Cu(I) enabled a high-yielding and rapid synthesis of a "Tn-antigen mimic" and click analogues of antifreeze glycopeptides, thus demonstrating a valuable synthetic platform for the synthesis of biologically relevant neoglycopeptides.
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Biomimetic studies towards the cardinalins: synthesis of (+)-ventiloquinone L and an unusual dimerisation.
Org. Biomol. Chem.
PUBLISHED: 04-28-2009
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Studies towards the biomimetic synthesis of cardinalin 3 are described. Despite the successful enantioselective synthesis of the monomeric pyranonaphthoquinone ventiloquinone L, it subsequently failed to undergo a proposed biomimetic homodimerisation to cardinalin 3 using a range of oxidants. However, treatment of a related naphthopyran with cerium ammonium nitrate (CAN) facilitated a tandem biaryl bond formation-oxidative demethylation sequence furnishing a dimeric pyranonaphthoquinone that had exclusively dimerised at C6. The nature of this unusual sequence is discussed and the product subsequently converted to the C6 regioisomer of cardinalin 3.
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Molecules derived from the extremes of life.
Nat Prod Rep
PUBLISHED: 04-21-2009
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In order to survive extremes of pH, temperature, salinity and pressure, organisms have been found to develop unique defences against their environment, leading to the biosynthesis of novel molecules ranging from simple osmolytes and lipids to complex secondary metabolites. This review highlights novel molecules isolated from microorganisms that either tolerate or favour extreme growth conditions.
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Synthesis of spiroacetal-nucleosides as privileged natural product-like scaffolds.
Org. Biomol. Chem.
PUBLISHED: 02-23-2009
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The elaboration of a 6,6-spiroacetal scaffold to incorporate a nucleoside unit at the anomeric position is described. The novel spiroacetal-nucleoside hybrids were generated via nucleosidation of acetoxy-spiroacetal with a series of silylated nucleobases under Vorbrüggen conditions.
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Synthesis of enantiopure bicyclic alpha,alpha-disubstituted spirolactams via asymmetric Birch reductive alkylation.
Org. Lett.
PUBLISHED: 02-10-2009
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The synthesis of enantiopure bicyclic alpha,alpha-disubstituted spirolactams is described using a diastereoselective Birch reductive alkylation as the key step. Hydrogenation of the resultant alkylated cyclohexadienes followed by intramolecular cyclization provides access to enantiopure 8-azaspiro[5.6]dodecan-7-ones.
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NNZ-2566: a Gly-Pro-Glu analogue with neuroprotective efficacy in a rat model of acute focal stroke.
J. Neurol. Sci.
PUBLISHED: 01-20-2009
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The N-terminal cleavage product of human insulin-like growth factor-1 (IGF-1) in the brain is the tripeptide molecule Glypromate (Gly-Pro-Glu). Glypromate has demonstrated neuroprotective effects in numerous in vitro and in vivo models of brain injury and is in clinical trials for the prevention of cognitive impairment following cardiac surgery. NNZ-2566 is a structural analogue of Glypromate, resulting from alpha-methylation of the proline moiety, which has improved the elimination half-life and oral bioavailability over the parent peptide. In vivo, NNZ-2566 reduces injury size in rats subjected to focal stroke. An intravenous infusion of NNZ-2566 of 4 h duration (3-10 mg/kg/h), initiated 3 h after endothelin-induced middle-cerebral artery constriction, significantly reduced infarct area as assessed on day 5. Neuroprotective efficacy in the MCAO model was also observed following oral administration of the drug (30-60 mg/kg), when formulated as a microemulsion. In vitro, NNZ-2566 significantly attenuates apoptotic cell death in primary striatal cultures, suggesting attenuation of apoptosis is one mechanism of action underlying its neuroprotective effects. NNZ-2566 is currently in clinical trials for the treatment of cognitive deficits following traumatic brain injury, and these data further support the development of the drug as a neuroprotective agent for acute brain injury.
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A novel approach to the CDE ring system of pectenotoxin-4 triggered by VO(acac)(2)-induced epoxy-acetalization.
Org. Lett.
PUBLISHED: 01-02-2009
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A novel approach to the CDE fragment of pectenotoxin-4 is described wherein the bicyclic acetal is constructed via a cascade cyclization induced by VO(acac)(2) epoxidation of a homoallylic alcohol.
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In vitro metabolism of norbormide in rat, mouse and guinea pig liver preparations.
Environ. Toxicol. Pharmacol.
PUBLISHED: 01-01-2009
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Differences between species in response to norbormide (NRB) may arise through differential pharmacodynamic and/or pharmacokinetic properties. We hypothesise that species-selectivity is at least partly determined by differences in metabolism based on in vitro data generated in liver preparations from rats, mice and guinea pigs. HPLC separation and LC/MS identification revealed that NRB undergoes metabolism primarily to hydroxylated form that was tentatively identified in both rat and non-rat species with NADPH as the preferred cofactor. However, the metabolic profile and the rate are different between species. Gender differences are also reported in the metabolic rate in rats and we postulate that this may be responsible for different toxic sensitivities seen between sexes. Using this knowledge, we aim to develop pharmacological tool(s) for use in designing a new class of drugs that can be targeted in a tissue-selective manner. Further in vivo pharmacokinetic with receptor affinity studies are warranted.
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Synthesis of the tetracyclic core of berkelic acid using gold(I)-catalyzed hydroarylation and oxidative radical cyclizations.
Org. Lett.
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A synthetic approach to the tetracyclic core of berkelic acid is reported using gold(I)-catalyzed intramolecular hydroarylation and oxidative radical cyclizations to effect the key ring-forming steps. The carboxylic acid was introduced via a late-stage palladium-catalyzed carbonylation to afford the core tetracycle with the correct relative stereochemistry for the natural product.
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Synthesis of the peptaibol framework of the anticancer agent culicinin D: stereochemical assignment of the AHMOD moiety.
Org. Lett.
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The postulated structure of the potent anticancer peptaibol culicinin D has been synthesized using Fmoc-based solid-phase peptide synthesis (SPPS). Comparison of the (1)H NMR data for the reported structure of culicinin D with the data obtained for the two synthetic polypeptides epimeric at C-6 in the AHMOD unit established the C-6 stereochemistry of the AHMOD residue in the natural product to be (R).
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Synthesis of monolysyl advanced glycation endproducts and their incorporation into collagen model peptides.
Org. Lett.
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The synthesis of advanced glycation endproducts (AGEs), CML, CEL, and pyrraline and their incorporation into collagen model peptides is reported. AGEs are modified amino acids that form on proteins such as collagen and are thought to play a significant role in the pathogenesis of many diseases, particularly diabetes. The synthesis and incorporation of these compounds into synthetic peptides is a key step in developing model systems with which to investigate AGE-modified proteins.
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Total synthesis of the initially reported and revised structures of the neuroprotective agent palmyrolide A.
Org. Lett.
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The total syntheses of the initially reported and revised structures of the neuroprotective agent palmyrolide A are reported. The key macrocyclization step was achieved using a sequential ring closing metathesis/olefin isomerization reaction. The synthetic work described herein serves to confirm the recent structural revision of this unusual natural product.
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Total synthesis of 7,8-dihydroaigialospirol.
Org. Lett.
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A highly convergent total synthesis of 7,8-dihydroaigialospirol is described. Key steps of the synthesis include a Nozaki-Hiyama-Kishi (NHK) coupling of an iodoalkyne with an advanced phthalide-aldehyde and a remarkable one-pot acid-mediated global deprotection/spiroacetalization.
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How to blast osteoblasts? Novel dicarba analogues of amylin-(1-8) to treat osteoporosis.
Bioorg. Med. Chem.
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When administered in vivo, amylin (1-8) stimulates osteoblast proliferation increasing bone volume and bone strength. The native cyclic octapeptide amylin (1-8) is unstable, however, it provides an attractive framework for the creation of more stable, orally active synthetic analogues using various peptidomimetic techniques. On-resin ring closing metathesis (RCM) on the olefinic side chains of allylglycine residues and lysine moieties functionalized with an allyloxycarbonyl (Alloc) group, was used to prepare novel carba-bridged surrogates of the disulfide bridge between Cys/2 and Cys/7 in amylin-(1-8). Commercially available N(?)-Fmoc N(?)-Alloc protected lysine was used as a convenient substrate for Grubbs ring closing metathesis. Analogues of amylin-(1-8) prepared by cyclization of allylglycine residues that also contained proline residues at either position 4 or 6, or both, were also prepared to investigate the effect of proline as a kink-inducing residue on the efficiency of the RCM reaction. Of the nine novel alkene-bridged analogues prepared, five showed promising biological activity in a proliferation study in primary foetal rat osteoblasts at physiological concentrations. Two of these analogues were chosen for further in vivo evaluation.
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N-alkylsulfonylimines as dipolarophiles in cycloaddition reactions.
Chem Asian J
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First described in the late 1960s, N-alkylsulfonylimines are heterocumulenes that participate in reactions with a range of 1,3-dipoles to afford interesting 3-, 4-, 5-, and 6-membered heterocycles. The distribution of adducts obtained suggests that multistage, stepwise mechanistic pathways rather than a concerted process are in operation.
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The Kulinkovich hydroxycyclopropanation reaction in natural product synthesis.
Org. Biomol. Chem.
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The Kulinkovich cyclopropanation reaction provides a flexible and convenient method for the synthesis of cyclopropanols. Together with the diverse chemistry of the cyclopropanol unit, it offers access to a wide range of functionalised unsaturated and saturated compounds. The successful use in the synthesis of natural compounds is outlined in this perspective.
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Synthesis and biological evaluation of tyrosine modified analogues of the ?4?7 integrin inhibitor biotin-R?ERY.
Bioorg. Med. Chem.
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The ?4?7 integrin is a well-known target for the development of drugs against various inflammatory disease states including inflammatory bowel disease, type 1 diabetes and multiple sclerosis. The synthesis of a small library of cell-permeable ?7 integrin inhibitors based on the peptide biotin-R(8)ERY is reported, in which the tyrosine residue has been modified by using the Suzuki-Miyaura cross-coupling reaction. The synthesised peptidomimetics were evaluated in a cell adhesion assay and shown to inhibit Mn(2+)-activated adhesion of mouse TK-1 T cells to mouse MAdCAM-1. All of the synthesised peptidomimetics are more active than our previously reported lead compound biotin-R(8)ERY with two of the analogues, 6 and 7, exhibiting IC(50) values of <15 ?M.
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