- Genetic incorporation of a metal-chelating amino acid as a probe for protein electron transfer
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ET encounters jellyfish: Through the incorporation of the metal-chelating amino acid pyTyr into green fluorescent protein (GFP) from jellyfish, photoinduced electron transfer (ET) from the GFP chromophore to a bound Cu II ion was shown to occur within one nanosecond in a distance-dependent manner. The crystal structure of GFP with pyTyr at a specific position shows the structural basis for the nanomolar binding affinity of pyTyr to CuII ions. Copyright
- Liu, Xiaohong,Li, Jiasong,Dong, Jianshu,Hu, Cheng,Gong, Weimin,Wang, Jiangyun
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p. 10261 - 10265,5
(2012)
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Read Online
- Total Synthesis and Bioactivity Mapping of Geodiamolide H
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The first total synthesis of the actin-stabilizing marine natural product geodiamolide H was achieved. Solid-phase based peptide assembly paired with scalable stereoselective syntheses of polyketide building blocks and an optimized esterification set the
- Arndt, Hans-Dieter,B??neck, Johanna,Bellstedt, Peter,Dahse, Hans-Martin,G?rls, Helmar,Küllmer, Florian,Nasufovi?, Veselin,Stallforth, Pierre
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supporting information
p. 11633 - 11642
(2021/07/02)
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- Synthesis of Pentacyclic Framework of Herquline A
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The highly strained bowl-shaped pentacyclic structure of herquline A has rendered it one of the most difficult problems in organic synthesis yet to be solved. The challenges associated with the synthesis of herquline A have been well documented in four Ph.D. dissertations and in multiple reports regarding syntheses of its structurally simpler congeners. Herein, we report the construction of the pentacyclic core of herquline A that contains both N10?C2 and C3?C3′ bonds. The key for success was the development of the tandem aza-Michael addition/enolate capture protocol that set the stage for subsequent palladium catalyzed C3(sp2)?C3′(sp2) coupling reaction. Ensuing oxidative dearomatization of the left aryl ring allowed the formation of the pentacyclic diketone core of herquline A.
- Kim, Thomas Taehyung,Lee, Chungwoo,Heo, Seongrok,Lee, Hee-Seung,Han, Sunkyu
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supporting information
p. 3882 - 3885
(2021/10/14)
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- Synthesis of the polyketide section of seragamide A and related cyclodepsipeptides via Negishi cross coupling
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The synthesis of the polyketide section present in the potently cytotoxic marine cyclodepsipeptide jasplakinolide and related natural products, geodiamolides and seragamides, is reported. The key step is a Negishi cross coupling of (R)-(3-methoxy-2-methyl
- Lang, Jan Hendrik,Lindel, Thomas
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supporting information
p. 577 - 583
(2019/03/08)
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- Concise Total Synthesis of Herqulines B and C
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A simple total synthesis of herqulines B and C is reported, modeled on the reductive biosynthesis reported previously by other researchers. Commencing from tyrosine, these alkaloids were fashioned through a dimerization, macrocyclization, and four consecu
- He, Chi,Stratton, Thomas P.,Baran, Phil S.
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supporting information
p. 29 - 32
(2019/01/16)
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- Structure-Activity Relationships of cyclo(l -Tyrosyl- l -tyrosine) Derivatives Binding to Mycobacterium tuberculosis CYP121: Iodinated Analogues Promote Shift to High-Spin Adduct
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A series of analogues of cyclo(l-tyrosyl-l-tyrosine), the substrate of the Mycobacterium tuberculosis enzyme CYP121, have been synthesized and analyzed by UV-vis and electron paramagnetic resonance spectroscopy and by X-ray crystallography. The introduction of iodine substituents onto cyclo(l-tyrosyl-l-tyrosine) results in sub-μM binding affinity for the CYP121 enzyme and a complete shift to the high-spin state of the heme FeIII. The introduction of halogens that are able to interact with heme groups is thus a feasible approach to the development of next-generation, tight binding inhibitors of the CYP121 enzyme, in the search for novel antitubercular compounds.
- Rajput, Sunnia,McLean, Kirsty J.,Poddar, Harshwardhan,Selvam, Irwin R.,Nagalingam, Gayathri,Triccas, James A.,Levy, Colin W.,Munro, Andrew W.,Hutton, Craig A.
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supporting information
p. 9792 - 9805
(2019/11/13)
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- Repurposing a Library of Human Cathepsin L Ligands: Identification of Macrocyclic Lactams as Potent Rhodesain and Trypanosoma brucei Inhibitors
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Rhodesain (RD) is a parasitic, human cathepsin L (hCatL) like cysteine protease produced by Trypanosoma brucei (T. b.) species and a potential drug target for the treatment of human African trypanosomiasis (HAT). A library of hCatL inhibitors was screened, and macrocyclic lactams were identified as potent RD inhibitors (Ki 50 400 nM). SARs addressing the S2 and S3 pockets of RD were established. Three cocrystal structures with RD revealed a noncovalent binding mode of this ligand class due to oxidation of the catalytic Cys25 to a sulfenic acid (Cys-SOH) during crystallization. The P-glycoprotein efflux ratio was measured and the in vivo brain penetration in rats determined. When tested in vivo in acute HAT model, the compounds permitted up to 16.25 (vs 13.0 for untreated controls) mean days of survival.
- Giroud, Maude,Dietzel, Uwe,Anselm, Lilli,Banner, David,Kuglstatter, Andreas,Benz, J?rg,Blanc, Jean-Baptiste,Gaufreteau, Delphine,Liu, Haixia,Lin, Xianfeng,Stich, August,Kuhn, Bernd,Schuler, Franz,Kaiser, Marcel,Brun, Reto,Schirmeister, Tanja,Kisker, Caroline,Diederich, Fran?ois,Haap, Wolfgang
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supporting information
p. 3350 - 3369
(2018/05/01)
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- LAT-1 activity of meta-substituted phenylalanine and tyrosine analogs
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The transporter protein Large-neutral Amino Acid Transporter 1 (LAT-1, SLC7A5) is responsible for transporting amino acids such as tyrosine and phenylalanine as well as thyroid hormones, and it has been exploited as a drug delivery mechanism. Recently its role in cancer has become increasingly appreciated, as it has been found to be up-regulated in many different tumor types, and its expression levels have been correlated with prognosis. Substitution at the meta position of aromatic amino acids has been reported to increase affinity for LAT-1; however, the SAR for this position has not previously been explored. Guided by newly refined computational models of the binding site, we hypothesized that groups capable of filling a hydrophobic pocket would increase binding to LAT-1, resulting in improved substrates relative to parent amino acid. Tyrosine and phenylalanine analogs substituted at the meta position with halogens, alkyl and aryl groups were synthesized and tested in cis-inhibition and trans-stimulation cell assays to determine activity. Contrary to our initial hypothesis we found that lipophilicity was correlated with diminished substrate activity and increased inhibition of the transporter. The synthesis and SAR of meta-substituted phenylalanine and tyrosine analogs is described.
- Augustyn, Evan,Finke, Karissa,Zur, Arik A.,Hansen, Logan,Heeren, Nathan,Chien, Huan-Chieh,Lin, Lawrence,Giacomini, Kathleen M.,Colas, Claire,Schlessinger, Avner,Thomas, Allen A.
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supporting information
p. 2616 - 2621
(2016/05/09)
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- Directed hydrogenations and an Ireland-Claisen rearrangement linked to Evans-Tishchenko chemistry: The highly efficient total synthesis of the marine cyclodepsipeptide doliculide
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Two new convergent total syntheses have been developed for the cytotoxic, actin microfilament-stabilizing marine cyclodepsipeptide doliculide (1). A key strategic element of both routes is the establishment of the central stereogenic center of the characteristic polydeoxypropionate stereotriad by means of a hydroxyl-directed catalytic hydrogenation of a trisubstituted double bond. The requisite olefin substrates were obtained through a modified Suzuki-Miyaura coupling or through Ireland-Claisen rearrangement of a propionate ester, respectively; the latter was the direct result of a highly selective Evans-Tishchenko reduction of a hydroxy ketone that had been obtained in a stereoselective Paterson aldol reaction. Doliculide (1) was finally obtained in a total number of 17 or 15 (14) linear steps, respectively, which represents a substantial improvement over previous syntheses of this highly bioactive natural product.
- Chen, Tao,Altmann, Karl-Heinz
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supporting information
p. 8403 - 8407
(2015/06/02)
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- Total synthesis of mycocyclosin
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The first total synthesis of mycocyclosin, a diketopiperazine natural product isolated from M. tuberculosis, is described. While direct oxidative coupling of tyrosine phenolic groups was unsuccessful, construction of the highly strained bicyclic framework was successfully accomplished through an intramolecular Miyaura-Suzuki cross-coupling to generate the biaryl linkage.
- Cochrane, James R.,White, Jonathan M.,Wille, Uta,Hutton, Craig A.
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supporting information; experimental part
p. 2402 - 2405
(2012/06/18)
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- Intramolecular suzuki-miyaura reaction for the total synthesis of signal peptidase inhibitors, arylomycins A2and B2
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Development of the total syntheses of arylomycins A1 and B 2 is detailed. Key features of our approach include 1) formation of 14-membered meta, meta-cyclophane by an intramolecular Suzuki-Miyaura reaction; 2) incorporation of N-Me-4-hydroxyphenylglycine into the cyclization precursor, which avoids the late-stage low-yielding N-methylation step; 3) segment coupling of a fully elaborated peptide side chain to the macrocycle, which makes the synthesis highly convergent. Overall, arylomycin A2 was obtained in 13 steps from L-Tyr for the longest linear sequence, in 13% overall yield. Arylomycin B2 was synthesized in 10 steps from L-3-nitro-Tyr, in 10% overall yield.
- Dufour, Jeremy,Neuville, Luc,Zhu, Jieping
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scheme or table
p. 10523 - 10534
(2010/11/04)
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- A convenient catalyst for aqueous and protein Suzuki-Miyaura cross-coupling
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(Figure Presented) A phosphine-free palladium catalyst for aqueous Suzuki-Miyaura cross-coupling is presented. The catalyst is active enough to mediate hindered, ortho-substituted biaryl couplings but mild enough for use on peptides and proteins. The Suzuki-Miyaura couplings on protein substrates are the first to proceed in useful conversions. Notably, hydrophobic aryl and vinyl groups can be transferred to the protein surface without the aid of organic solvent since the aryl- and vinylboronic acids used in the coupling are water-soluble as borate salts. The convenience and activity of this catalyst prompts use in both general synthesis and bioconjugation.
- Chalker, Justin M.,Wood, Charlotte S. C.,Davis, Benjamin G.
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supporting information; experimental part
p. 16346 - 16347
(2010/01/29)
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- Thieme Chemistry Journal awardees - Where are they now? Scope of tyrosine O-arylations with boronic acids: Optimized synthesis of an orthogonally protected isodityrosine
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The Evans-Chan-Lam variant of the Ullman condensation has been explored to deliver O-arylated tyrosines and tyrosinyl peptides. Key modifications for success were the slow addition of boronic acids to the phenol-catalyst mixture. Selectivity and scope are investigated. Georg Thieme Verlag Stuttgart.
- Kilitoglu, Bahar,Arndt, Hans-Dieter
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scheme or table
p. 720 - 723
(2009/08/07)
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- Solid-phase synthesis of 5-arylhistidines via a microwave-assisted Suzuki-Miyaura cross-coupling
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Microwave irradiation efficiently promoted the solid-phase Suzuki-Miyaura reaction of a 5-bromohistidine with various arylboronic acids in the presence of a palladium catalyst. This methodology allowed the synthesis of peptides bearing a histidine residue substituted at position 5 of the imidazole ring with a phenyl, a substituted phenyl, a pyridyl, or a thienyl ring, as well as with the benzene ring of a tyrosine residue.
- Cerezo, Vanessa,Amblard, Muriel,Martinez, Jean,Verdié, Pascal,Planas, Marta,Feliu, Lidia
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p. 10538 - 10545
(2008/12/22)
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- Efficient enantioselective synthesis of condensed and aromatic-ring- substituted tyrosine derivatives
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An efficient access to both condensed and conjugated tyrosine analogues of high enantiomeric purity is described. Novel ring-substituted tyrosines were synthesized by Suzuki cross couplings of appropriately protected L-3-iodotyrosine with a series of activated and deactivated boronic acid derivatives to achieve the target compounds in high yields. D- and L-4-hydroxy-1-naphthylalanines were readily prepared from the corresponding α-enamide in two different approaches, by asymmetric hydrogenation as well as by unselective hydrogenation and enzymatic resolution of the racemic mixture.
- Knoer, Sebastian,Laufer, Burkhardt,Kessler, Horst
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p. 5625 - 5630
(2007/10/03)
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- Synthesis of tyrosine derivatives for saframycin MX1 biosynthetic studies
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Saframycin MX1 and structural relatives are natural anticancer agents isolated from bacteria and marine invertebrates. For biosynthetic studies and to make a library of modified natural products, a series of tyrosine derivatives were synthesized in a conc
- Schmidt, Eric W.,Nelson, James T.,Fillmore, John P.
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p. 3921 - 3924
(2007/10/03)
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- Use of a boroxazolidone complex of 3-iodo-l-tyrosine for palladium-catalyzed cross-coupling
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Complexation of 3-iodo-L-tyrosine with 9-borabicyclo[3.3.1]nonane (9-BBN) provides a convenient substrate for a palladium-catalyzed coupling reaction. The complex is stable to silica gel chromatography (hexanes/ethyl acetate), dilute triethylamine in THF, and potassium fluoride in DMF. The desired product, 3-ethynyl-L-tyrosine, was released from the complex by simply diluting its solution in methanol with chloroform. Interestingly, the complex remains stable in solutions of either methanol or chloroform individually.
- Walker IV, William H.,Rokita, Steven E.
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p. 1563 - 1566
(2007/10/03)
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- Synthesis of the (S,S,S)-diastereomer of the 15-membered biaryl ring system of RP 66453
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The synthesis of the 15-membered biaryl ring system constituting an appropriately functionalized AB ring system of RP 66453 is detailed.
- Krenitsky, Paul J.,Boger, Dale L.
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p. 4019 - 4022
(2007/10/03)
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- Inhibitors of protein tyrosine phosphatase
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The present invention comprises small molecular weight, non-peptidic inhibitors of formulae I-VII of Protein Tyrosine Phosphatase 1 (PTP1) which are useful for the treatment and/or prevention of Non-Insulin Dependent Diabetes Mellitus (NIDDM).
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- Synthesis and biological activity of a novel class of small molecular weight peptidomimetic competitive inhibitors of protein tyrosine phosphatase 1B
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Protein tyrosine phosphatase 1B (PTP1B) negatively regulates insulin signaling in part by dephosphorylating key tyrosine residues within the regulatory domain of the β-subunit of the insulin receptor (IR), thereby attenuating receptor tyrosine kinase acti
- Larsen, Scott D.,Barf, Tjeerd,Liljebris, Charlotta,May, Paul D.,Ogg, Derek,O'Sullivan, Theresa J.,Palazuk, Barbara J.,Schostarez, Heinrich J.,Stevens, F. Craig,Bleasdale, John E.
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p. 598 - 622
(2007/10/03)
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- Preparation of phosphatase inhibitors
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Disclosed are compounds of the Formula I and pharmaceutically acceptable salts and prodrugs thereof, wherein A, B, R1, R2, R3, R4 and R5 are as defined in the specification. Such compounds are tyrosine phosphatase inhibitors and useful in the treatment or prevention of Type II Diabetes Mellitus. Also encompassed by the invention are formulations comprising the noted compounds, processes for preparing such compounds, a method for treating or preventing Type II Diabetes Mellitus.
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- Entry into the bi-aryl moiety of the TMC-95 proteasome inhibitors via the Stille protocol
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The synthesis of the bi-aryl moiety of the TMC-95 natural products has been achieved via a palladium-catalyzed Stille cross-coupling reaction of an aryl stannane tyrosine derivative and 7-iodoisatin.
- Albrecht, Brian K.,Williams, Robert M.
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p. 2755 - 2757
(2007/10/03)
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