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Find video protocols related to scientific articles indexed in Pubmed.
Highly efficient and selective phosphorylation of amino acid derivatives and polyols catalysed by 2-aryl-4-(dimethylamino)pyridine-N-oxides - towards kinase-like reactivity.
Chem. Commun. (Camb.)
PUBLISHED: 09-24-2014
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The chemoselective phosphorylation of hydroxyl containing amino acid derivatives and polyols by phosphoryl chlorides catalyzed by 2-aryl-4-(dimethylamino)pyridine-N-oxides is described.
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A bioorthogonal (68)Ga-labelling strategy for rapid in vivo imaging.
Chem. Commun. (Camb.)
PUBLISHED: 07-12-2014
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Herein, we describe a fast and robust method for achieving (68)Ga-labelling of the EGFR-selective monoclonal antibody (mAb) Cetuximab using the bioorthogonal Inverse-electron-Demand Diels-Alder (IeDDA) reaction. The in vivo imaging of EGFR is demonstrated, as well as the translation of the method within a two-step pretargeting strategy.
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Improving the accuracy of computed 13C NMR shift predictions by specific environment error correction: fragment referencing.
J. Org. Chem.
PUBLISHED: 11-06-2013
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The accuracy of both Gauge-including atomic orbital (GIAO) and continuous set of gauge transformations (CSGT) (13)C NMR spectra prediction by Density Functional Theory (DFT) at the B3LYP/6-31G** level is shown to be usefully enhanced by employing a fragment referencing method for predicting chemical shifts without recourse to empirical scaling. Fragment referencing refers to a process of reducing the error in calculating a particular NMR shift by consulting a similar molecule for which the error in the calculation is easily deduced. The absolute accuracy of the chemical shifts predicted when employing fragment referencing relative to conventional techniques (e.g., using TMS or MeOH/benzene dual referencing) is demonstrated to be improved significantly for a range of substrates, which illustrates the superiority of the technique particularly for systems with similar chemical shifts arising from different chemical environments. The technique is particularly suited to molecules of relatively low molecular weight containing non-standard magnetic environments, e.g., ? to halogen atoms, which are poorly predicted by other methods. The simplicity and speed of the technique mean that it can be employed to resolve routine structural assignment problems that require a degree of accuracy not provided by standard incremental or hierarchically ordered spherical description of environment (HOSE) algorithms. The approach is also demonstrated to be applicable when employing the MP2 method at 6-31G**, cc-pVDZ, aug-cc-pVDZ, and cc-pVTZ levels, although none of these offer advantage in terms of accuracy of prediction over the B3LYP/6-31G** DFT method.
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Preclinical evaluation of a CXCR4-specific (68)Ga-labelled TN14003 derivative for cancer PET imaging.
Bioorg. Med. Chem.
PUBLISHED: 09-11-2013
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Molecular imaging is an ideal platform for non-invasive detection and assessment of cancer. In recent years, the targeted imaging of CXCR4, a chemokine receptor that has been associated with tumour metastasis, has become an area of intensive research. In our pursuit of a CXCR4-specific radiotracer, we designed and synthesised a novel derivative of the CXCR4 peptidic antagonist TN14003, CCIC16, which is amenable to radiolabelling by chelation with a range of PET and SPECT radiometals, such as (68)Ga, (64)Cu and (111)In as well as (18)F (Al(18)F). Potent in vitro binding affinity and inhibition of signalling-dependent cell migration by unlabelled CCIC16 were confirmed by a threefold uptake in CXCR4-over-expressing cells compared to their isogenic counterparts. Furthermore, in vivo experiments demonstrated the favourable pharmacokinetic properties of the (68)Ga-labelled tracer (68)Ga-CCIC16, along with its CXCR4-specific accumulation in tissues with desirable contrast (tumour-to-muscle ratio: 9.5). The specificity of our tracer was confirmed by blocking experiments. Taking into account the attractive intrinsic PET imaging properties of (68)Ga, the comprehensive preclinical evaluation presented here suggests that (68)Ga-CCIC16 is a promising PET tracer for the specific imaging of CXCR4-expressing tumours.
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Synthesis of a new fluorine-18 glycosylated click cyanoquinoline for the imaging of epidermal growth factor receptor.
J Labelled Comp Radiopharm
PUBLISHED: 08-29-2013
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This study reports the radiosynthesis of a new fluorine-18 glycosylated click cyanoquinoline [(18) F]5 for positron emission tomography imaging of epidermal growth factor receptor (EGFR). The tracer was obtained in 47.7?±?7.5% (n?=?3) decay-corrected radiochemical yield from 2-[(18) F]fluoro-2-deoxy-?-d-glucopyranosyl azide, and the overall nondecay-corrected radiochemical yield from aqueous fluoride was 8.6?±?2.3% (n?=?3). An in vitro preliminary cellular uptake study showed selectivity of the tracer for EGFR-positive A431 cell lines versus EGFR-negative MCF-7 cell lines. [(18) F]5 tracer uptake in A431 cells was significantly reduced by addition of the cold isotope analogue compound 5.
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Development of small molecules to target the IgE:Fc?RI protein-protein interaction in allergies.
Future Med Chem
PUBLISHED: 08-08-2013
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The protein-protein interaction (PPI) between IgE and its high-affinity receptor (Fc?RI) is a key component of the allergic response. Inhibiting the IgE:Fc?RI PPI is an attractive strategy for therapeutic intervention and the development of allergy treatments. This PPI has been validated as a viable target by the monoclonal anti-IgE antibody omalizumab (Xolair(®)), which has demonstrated clinical efficacy when prescribed to treat moderate-to-severe asthma and hay fever, but small molecules would be a more convenient form of treatment. Cyclic peptides, small proteins and a natural product have all been developed to target the IgE:Fc?RI PPI, and these will be discussed in this review. Targeting the IgE:Fc?RI complex with small molecules presents various challenges, some of which are inherent in all PPI targets but some of which are unique to this system, which presents great opportunities for the development of new therapeutics for the treatment of allergies.
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Bioorthogonal chemistry for pre-targeted molecular imaging--progress and prospects.
Org. Biomol. Chem.
PUBLISHED: 08-03-2013
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The aim of this perspective is to critically review the three most prominent bioorthogonal reactions that are used presently, on both a purely chemical level and in the context of biological systems. This includes the uses both for synthesis of therapeutic molecules, modification of large biomolecules or antibodies, and in particular, the exciting use in the field of pre-targeting, for both possible treatment and imaging technologies. We will compare the validity of each reaction when compared to others, and their usefulness in biological systems, as each methodology has clear advantages over the others in differing environments.
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Structural assignment of a bis-cyclopentenyl-?-cyanohydrin formed via alkene metathesis from either a triene or a tetraene precursor.
Acta Crystallogr C
PUBLISHED: 07-30-2013
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The identity of the major product of Ru-catalysed alkene metathesis of two polyene substrates has been determined using density functional theory (DFT) NMR prediction, a (1)H-(1)H Total Correlated Spectroscopy (TOCSY) NMR experiment and ultimately by single-crystal X-ray crystallography. The substrates were designed as those that would potentially allow expedient access to the trans-decalin skeleton of the natural product (-)-euonyminol, but the product was found to be a bis-cyclopentenyl-?-cyanohydrin [1-(1-hydroxycyclopent-3-en-1-yl)cyclopent-3-ene-1-carbonitrile, C11H13NO] rather than the trans-2,3,6,7-dehydrodecalin-?-cyanohydrin.
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Bioorthogonal chemistry for (68) Ga radiolabelling of DOTA-containing compounds.
J Labelled Comp Radiopharm
PUBLISHED: 06-04-2013
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Copper-catalysed click chemistry is a highly utilised technique for radiolabelling small molecules and peptides for imaging applications. The usefulness of these reactions falls short, however, when metal catalysis is not a practically viable route; such as when using metal chelates as radioligands. Here, we describe a method for carrying out click-type radiochemistry in the presence of DOTA chelates, by combining (68) Ga radiolabelling techniques with well-established bioorthogonal reactions, which do not rely upon metal catalysis.
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Towards the enantioselective synthesis of (-)-euonyminol--preparation of a fully functionalised lower-rim model.
Org. Biomol. Chem.
PUBLISHED: 02-26-2013
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The development of a stereoselective total synthesis of ?-dihydroagarofuran 4 is described. This compound contains the same oxygenation pattern on its lower-rim as found in the natural sesquiterpene (-)-euonyminol (1) and it is expected that the route described should be applicable to the synthesis of that complex natural product. (-)-Euonyminol is found as the core scaffold of a series of complex macrodilactone sesquiterpenoids isolated from the Celastraceae which possess interesting biological activities (e.g. anti-HIV activity). The synthetic route builds upon an epoxidative asymmetric desymmetrisation of meso-diallylic alcohol 10 that we have reported previously. It features a lactate Ireland-Claisen rearrangement to establish the quaternary stereocentre at C11 (27?28a) and an unusual dealkylative intramolecular epoxide-opening by the C11 methyl ether to establish the tetrahydrofuranyl C-ring of the ?-dihydroagarofuran skeleton (35?36).
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Copper-free click--a promising tool for pre-targeted PET imaging.
Chem. Commun. (Camb.)
PUBLISHED: 12-07-2011
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The copper-free click (CFC) reaction has been evaluated for its potential application to in vivo pre-targeting for PET imaging. A promising biodistribution profile is demonstrated when employing [(18)F]2-fluoroethylazide ([(18)F]1) and optimisation of the CFC reaction with a series of cyclooctynes shows that reactions proceed efficiently with tantalizing opportunities for application-specific tuning.
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Synthesis of the C19 methyl ether of aspercyclide A via germyl-Stille macrocyclisation and ELISA evaluation of both enantiomers following optical resolution.
Org. Biomol. Chem.
PUBLISHED: 08-15-2011
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Aspercyclide A (1) is a biaryl ether containing 11-membered macrocyclic natural product antagonist of the human IgE-Fc?RI protein-protein interaction (PPI); a key interaction in the signal transduction pathway for allergic disorders such as asthma. Herein we report a novel approach to the synthesis of the C19 methyl ether of aspercyclide A, employing a Pd(0)-catalysed, fluorous-tagged alkenylgermane/arylbromide macrocyclisation (germyl-Stille reaction) as the key step, and evaluation of both enantiomers of this compound via ELISA following optical resolution by CSP-HPLC. A crystal structure for germyl hydride 27 is also reported.
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Total synthesis of the Amaryllidaceae alkaloid clivonine.
Org. Biomol. Chem.
PUBLISHED: 03-02-2011
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Two syntheses of the Amaryllidaceae alkaloid clivonine (1) are described. Both employ previously reported 7-arylhydrindane 6 as an intermediate but differ in the method employed for subsequent introduction of what becomes the ring-B lactone carbonyl carbon (C7). The synthesis featuring a Bischler-Napieralski reaction for this transformation constitutes the first asymmetric synthesis of natural (+)-clivonine. Crystal structures for compounds (±)-13, (±)-16, (-)-20 and (±)-28 are also reported.
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(±)-trans,cis-4-Hydroxy-5,6-di-O-isopropylidenecyclohex-2-ene-1-one: synthesis and facile dimerization to decahydrodibenzofurans.
J. Org. Chem.
PUBLISHED: 01-25-2011
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An efficient synthesis of (±)-trans,cis-4-hydroxy-5,6-di-O-isopropylidenecyclohex-2-ene-1-one (3) has been developed from acetonide-protected meso-1,2-dihydrocatechol derivative 1 via photooxygenation, then Kornblum-DeLaMare rearrangement. The product is unstable unless its 4-hydroxy group is protected, as it undergoes facile dimerization in solution to a 1:1 mixture of diastereoisomeric decahydrodibenzofurans 8 and 9. A new synthesis of the dihydrocatechol 1 from 1,3-cyclohexadiene has also been developed.
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A method for parallel solid-phase synthesis of iodinated analogs of the cannabinoid receptor type I (CB?) inverse agonist rimonabant.
Meth. Enzymol.
PUBLISHED: 11-06-2010
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Rimonabant (acomplia) is a 1,5-diarylpyrazole derivative that acts as a type 1 cannabinoid receptor (CB?) inverse agonist. Here, we overview the role of this type of molecule in regulation of these receptors and their potential as starting points for the development of molecular probes to image the central nervous system (CNS). We then describe a novel protocol for the solid-phase parallel chemical synthesis of iodinated rimonabant analogs using germanium-functionalized, cross-linked polystyrene as the solid-support (or "resin"). The method allows for rapid derivatization at the key C-3 position of rimonabant from a common resin-bound precursor. The desired iodinated analogs are then obtained by ipso-iododegermylative cleavage from the resin using sodium iodide/N-chlorosuccinimide (NCS) in a fashion that ought to be readily adapted to the rapid preparation of isotopically labeled iodine derivatives for molecular imaging of CNS activity by positron emission tomography (PET, using ¹²?I) and single photon emission computerized tomography (SPECT, using (¹²³I) techniques. Toward this goal, we also show that the NCS-derived succinimide by-product that is released from the resin concomitantly with the potential imaging probe molecules can be readily and selectively removed by treatment of the crude soluble product mixture with a solid-supported hydrazide scavenger resin.
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The liver receptor homolog-1 regulates estrogen receptor expression in breast cancer cells.
Breast Cancer Res. Treat.
PUBLISHED: 06-08-2010
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Estrogen receptor-? (ER) is expressed in the great majority of breast cancers, and the inhibition of ER action is a key part of breast cancer treatment. The inhibition of ER action is achieved using anti-estrogens, primarily tamoxifen, and with aromatase inhibitors that inhibit estrogen biosynthesis, thereby preventing ER activation. However, resistance to these therapies is common. With the aim of identifying new molecular targets for breast cancer therapy, we have identified the liver receptor homolog-1 (LRH-1) as an estrogen-regulated gene. RNA interference and over-expression studies were used to investigate the role of the LRH-1 in regulating breast cancer growth and to identify the targets of an LRH-1 action. Promoter recruitment was determined using reporter gene and chromatin immunoprecipitation (ChIP) assays. We show that LRH-1 regulates breast cancer cell growth by regulating the ER expression. Reporter gene and in vitro DNA-binding assays identified an LRH-1-binding site in the ER gene promoter, and ChIP assays have demonstrated in vivo binding at this site. We also provide evidence for new LRH-1 variants in breast cancer cells arising from the use of alternative promoters. Previous studies have shown that LRH-1 functions in estrogen biosynthesis by regulating aromatase expression. Our findings extend this by highlighting LRH-1 as a key regulator of the estrogen response in breast cancer cells through the regulation of ER expression. Hence, inhibition of LRH-1 could provide a powerful new approach for the treatment of endocrine-resistant breast cancer.
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Total synthesis of the lycorenine-type amaryllidaceae alkaloid (+/-)-clivonine via a biomimetic ring-switch from a lycorine-type progenitor.
J. Am. Chem. Soc.
PUBLISHED: 03-19-2010
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A fully diastereoselective total synthesis of the lycorenine-type Amaryllidaceae alkaloid (+/-)-clivonine (19) is reported via a route that employs for the first time a biomimetic ring-switch from a lycorine-type progenitor, thereby corroborating experimentally the biogenetic hypothesis first expounded for these compounds by Barton in 1960.
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Development of a new epidermal growth factor receptor positron emission tomography imaging agent based on the 3-cyanoquinoline core: synthesis and biological evaluation.
Bioorg. Med. Chem.
PUBLISHED: 02-26-2010
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The epidermal growth factor receptor (EGFR/c-ErbB1/HER1) is overexpressed in many cancers including breast, ovarian, endometrial, and non-small cell lung cancer. An EGFR specific imaging agent could facilitate clinical evaluation of primary tumors and/or metastases. To achieve this goal we designed and synthesized a small array of fluorine containing compounds based on a 3-cyanoquinoline core. A lead compound, 16, incorporating 2-fluoroethyl-1,2,3-triazole was selected for evaluation as a radioligand based on its high affinity for EGFR kinase (IC50=1.81+/-0.18 nM), good cellular potency (IC50=21.97+/-9.06 nM), low lipophilicity and good metabolic stability. Click labeling afforded [18F]16 in 37.0+/-3.6% decay corrected radiochemical yield based on azide [18F]14 and 7% end of synthesis (EOS) yield from aqueous fluoride. Compound [18F]16 was obtained with >99% radiochemical purity in a total synthesis time of 3 h. The compound showed good stability in vivo and a fourfold higher uptake in high EGFR expressing A431 tumor xenografts compared to low EGFR expressing HCT116 tumor xenografts. Furthermore, the radiotracer could be visualized in A431 tumor bearing mice by small animal PET imaging. Compound [18F]16 therefore constitutes a promising radiotracer for further evaluation for imaging of EGFR status.
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Stereoselective synthesis of cis- and trans-2,3-disubstituted tetrahydrofurans via oxonium-prins cyclization: access to the cordigol ring system.
Org. Lett.
PUBLISHED: 02-11-2010
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SnBr(4)-promoted oxonium-Prins cyclizations to form 2,3-disubstituted tetrahydrofurans (THFs) are reported. In the absence of an internal nucleophile, the carbocation intermediates are trapped by bromide to give 2,3-cis- and 2,3-trans-configured products; two variations with intramolecular trapping are also reported. One of these allows a single-step stereocontrolled synthesis of the core 2,3-cis-THF ring system of cordigol, a fungicidal polyphenol from the stem bark of Cordia goetzei. For this latter transformation, a stepwise oxonium-Prins/cation trapping pathway rather than orthoquinonemethide formation/hetero-Diels-Alder cycloaddition is supported computationally.
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Total synthesis of (+/-)-aspercyclide A and its C19 methyl ether.
Chem. Commun. (Camb.)
PUBLISHED: 12-23-2009
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The total syntheses of (+/-)-aspercyclide A (1) and its C19 methyl ether (15a) featuring Heck-Mizoroki macrocyclisation to form the 11-membered (E)-styrenyl biaryl ether lactone core are described.
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A method for parallel solid-phase synthesis of iodinated analogues of the CB1 receptor inverse agonist rimonabant.
Org. Lett.
PUBLISHED: 09-26-2009
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A method for the parallel solid-phase synthesis (SPS) of iodinated analogues of Sanofi-Aventis type 1 cannabinoid (CB1) receptor inverse agonist rimonabant (acomplia) has been developed. The method allows the synthesis of a range of C3 amide/hydrazide derivatives from a resin-bound C3 ester precursor. The C-Ge linkage to the Hypogel-200 resin is stable to the diversification conditions but allows ipso-iododegermylative cleavage using NaI/NCS even for the products containing the oxidatively labile hydrazide moiety.
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Synthesis of anti and syn hydroxy-iso-evoninic acids.
Org. Biomol. Chem.
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The first synthesis of hydroxy-iso-evoninic acid (2), a pyridyl diacid found as a macrodilactone bridging ligand in bioactive Celastraceae sesquiterpenoid-based natural products, has been achieved in 9 steps and an overall yield of 26%. The synthesis utilizes a benzilic ester rearrangement (BER) and a late stage benzylic oxidation to give access to all four stereoisomers whose absolute stereochemistry was assigned following chromatographic separation and anomalous dispersion X-ray crystallography.
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Theoretical prediction of selectivity in kinetic resolution of secondary alcohols catalyzed by chiral DMAP derivatives.
J. Am. Chem. Soc.
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The mechanism of esterification of the secondary alcohol 1-(1-naphthyl)ethanol 9 by isobutyric anhydride catalyzed by 4-pyrrolidinopyridine (PPY, 11) and a series of single enantiomer atropisomeric 4-dialkylaminopyridines 8a-g has been studied computationally at the B3LYP/6-311+G(d,p)//B3LYP/6-31G(d) level. Comparison of the levels of enantioselectivity predicted computationally with the results obtained experimentally allowed the method to be validated. The value of the approach is demonstrated by the successful prediction that a structural modification of an aryl group within the catalyst from phenyl to 3,5-dimethylphenyl would lead to improved levels of selectivity in this type of kinetic resolution (KR) reaction, as was subsequently verified following synthesis and evaluation of this catalyst (8d). Experimentally, the selectivity of this type of KR is found to exhibit a significant deuterium isotope effect (for 9 vs d(1)-9).
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Synthesis and incorporation into cyclic peptides of tolan amino acids and their hydrogenated congeners: construction of an array of A-B-loop mimetics of the C?3 domain of human IgE.
J. Org. Chem.
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The disruption of the human immunolobulin E-high affinity receptor I (IgE-Fc?RI) protein-protein interaction (PPI) is a validated strategy for the development of anti asthma therapeutics. Here, we describe the synthesis of an array of conformationally constrained cyclic peptides based on an epitope of the A-B loop within the C?3 domain of IgE. The peptides contain various tolan (i.e., 1,2-biarylethyne) amino acids and their fully and partially hydrogenated congeners as conformational constraints. Modest antagonist activity (IC(50) ?660 ?M) is displayed by the peptide containing a 2,2-tolan, which is the one predicted by molecular modeling to best mimic the conformation of the native A-B loop epitope in IgE.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.