- Electron-deficient p-benzoyl-l-phenylalanine derivatives increase covalent chemical capture yields for protein–protein interactions
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The photoactivatable amino acid p-benzoyl-l-phenylalanine (pBpa) has been used for the covalent capture of protein–protein interactions (PPIs) in vitro and in living cells. However, this technique often suffers from poor photocrosslinking yields due to th
- Joiner, Cassandra M.,Breen, Meghan E.,Mapp, Anna K.
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- Facile synthesis of a novel genetically encodable fluorescent α-amino acid emitting greenish blue light
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We report the facile synthesis and characterization of a novel fluorescent α-amino acid 4-phenanthracen-9-yl-l-phenylalanine (Phen-AA) (5) that emits greenish blue light in the visible region. This genetically encodable l-α-amino acid has excellent photostability with a 75% quantum yield. It readily gets into human cells, being clearly imaged upon 405 nm laser excitation. The synthetic procedure is resistant to racemization and only involves three simple steps which use mild conditions and generate the Phen-AA in reasonably good yield. It may find broad applications in research, biotechnology, and the pharmaceutical industry.
- Gupta, Aakash,Garreffi, Brian P.,Guo, Maolin
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- A Bifunctional Amino Acid Enables Both Covalent Chemical Capture and Isolation of in Vivo Protein–Protein Interactions
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In vivo covalent chemical capture by using photoactivatable unnatural amino acids (UAAs) is a powerful tool for the identification of transient protein–protein interactions (PPIs) in their native environment. However, the isolation and characterization of
- Joiner, Cassandra M.,Breen, Meghan E.,Clayton, James,Mapp, Anna K.
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- Solid-phase, Pd-catalyzed silicon-aryl carbon bond formation. Synthesis of sansalvamide A peptide.
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A palladium-catalyzed silicon-aryl carbon bond formation on solid-phase is reported. A phenylalanine silane resin was prepared directly from protected iodo-substituted phenylalanine with butyl diethylsilane polystyrene in one step. A rapid and high-yield solid-phase synthesis of sansalvamide A peptide was achieved from the phenylalanine silane resin. [reaction: see text]
- Gu, Wenxin,Liu S, Shouxin,Silverman, Richard B
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- Sequence Programming with Dynamic Boronic Acid/Catechol Binary Codes
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The development of a synthetic code that enables a sequence programmable feature like DNA represents a key aspect toward intelligent molecular systems. We developed herein the well-known dynamic covalent interaction between boronic acids (BAs) and catechols (CAs) into synthetic nucleobase analogs. Along a defined peptide backbone, BA or CA residues are arranged to enable sequence recognition to their complementary strand. Dynamic strand displacement and errors were elucidated thermodynamically to show that sequences are able to specifically select their partners. Unlike DNA, the pH dependency of BA/CA binding enables the dehybridization of complementary strands at pH 5.0. In addition, we demonstrate the sequence recognition at the macromolecular level by conjugating the cytochrome c protein to a complementary polyethylene glycol chain in a site-directed fashion.
- Hebel, Marco,Riegger, Andreas,Zegota, Maksymilian M.,Kizilsavas, G?nül,Ga?anin, Jasmina,Pieszka, Michaela,Lückerath, Thorsten,Coelho, Jaime A. S.,Wagner, Manfred,Gois, Pedro M. P.,Ng, David Y. W.,Weil, Tanja
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- A facile solution and solid phase synthesis of phosphotyrosine mimetic L-4-[diethylphosphono(difluoromethyl)]-phenylalanine (F2Pmp(EtO)2) derivatives
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The F2Pmp derivatives were prepared in 80-90% yield from commercially available protected L-4-iodophenylalanine by esterification with diazomethane followed by a CuCl-mediated coupling to (diethylphosphonyl) difluoromethylcadmium bromide. Moreover, treatment of L-4-iodoPhe-containing peptides under the same coupling conditions provided the F2Pmp-containing peptides in very good yields.
- Qabar, Maher N.,Urban, Jan,Kahn, Michael
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- Synthesis and protein incorporation of azido-modified unnatural amino acids
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Two new azidophenylalanine residues (3 and 4) have been synthesized and, in combination with 4-azido-l-phenylalanine (1) and 4-azidomethyl-l-phenylalanine (2), form a series of unnatural amino acids (UAAs) containing the azide vibrational reporter at varying distances from the aromatic ring of phenylalanine. These UAAs were designed to probe protein hydration with high spatial resolution by utilizing the large extinction coefficient and environmental sensitivity of the azide asymmetric stretch vibration. The sensitivity of the azide reporters was investigated in solvents that mimic distinct local protein environments. Three of the four azido-modified phenylalanine residues were successfully genetically incorporated into a surface site in superfolder green fluorescent protein (sfGFP) utilizing an engineered, orthogonal aminoacyl-tRNA synthetase in response to an amber codon with high efficiency and fidelity. SDS-PAGE and ESI-Q-TOF mass analysis verified the site-specific incorporation of these UAAs. The observed azide asymmetric stretch in the linear IR spectra of these UAAs incorporated into sfGFP indicated that the azide groups were hydrated in the protein.
- Tookmanian, Elise M.,Fenlon, Edward E.,Brewer, Scott H.
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- A palladium and gold catalytic system enables direct access to O- and S-linked non-natural glyco-conjugates
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Here we report a straightforward cross-coupling method for the synthesis of non-natural glycoamino acids from alkyne-bearing monosaccharides and p-iodophenylalanine. Pd/Au-catalyzed Sonogashira coupling is tolerant to both O- and S-glycosides without any epimerization. In addition, no racemization of the amino acid was observed allowing direct access to the homogeneous glyco-conjugate in a single step. Notably, this Pd/Au catalytic system presents enhanced catalytic activity than conventional Pd/Cu and Pd-only platforms, and it further enables the convergent synthesis of glycodipeptides.
- Jeon, Min Ho,Mathew, Bijoy P.,Kuram, Malleswara Rao,Myung, Kyungjae,Hong, Sung You
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- Preparation method of sacubitril intermediate
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The invention relates to the technical field of synthesis of medical intermediates, in particular to a preparation method of a sacubitril intermediate, which comprises the following steps: 1) reacting a raw material compound III with phosphorus trihalide to obtain a compound II; and 2) reacting the compound II with phenylhydrazine in the presence of a catalyst and an additive to obtain a sacubitril intermediate, namely a compound I. According to the invention, cheap phosphorus trihalide is selected to replace expensive and highly toxic trifluoromethanesulfonic anhydride, and cheap phenylhydrazine and a catalyst palladium chloride are adopted. The method has the advantages of simple reaction operation, low cost and high yield, and is easier for industrial production of the compound I.
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Paragraph 0043-0044; 0046-0047
(2021/04/17)
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- Nickel-Catalyzed Asymmetric Synthesis of α-Arylbenzamides
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A nickel-catalyzed asymmetric reductive hydroarylation of vinyl amides to produce enantioenriched α-arylbenzamides is reported. The use of a chiral bisimidazoline (BIm) ligand, in combination with diethoxymethylsilane and aryl halides, enables the regioselective introduction of aryl groups to the internal position of the olefin, forging a new stereogenic center α to the N atom. The use of neutral reagents and mild reaction conditions provides simple access to pharmacologically relevant motifs present in anticancer, SARS-CoV PLpro inhibitors, and KCNQ channel openers.
- Cuesta-Galisteo, Sergio,Sch?rgenhumer, Johannes,Wei, Xiaofeng,Merino, Estíbaliz,Nevado, Cristina
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p. 1605 - 1609
(2020/12/01)
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- Total Synthesis of Seongsanamide B
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The first total synthesis of the bicyclic depsipeptide natural product seongsanamide B is described. The successful approach employed solid-phase peptide synthesis of a core heptapeptide, incorporating on-resin esterification, followed by solution-phase macrolactamization and a late stage intramolecular Evans-Chan-Lam coupling to generate the biaryl ether of the isodityrosine unit.
- Hutton, Craig A.,Shabani, Sadegh
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supporting information
(2020/06/05)
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- Electrochemical synthesis of 1,2-diketones from alkynes under transition-metal-catalyst-free conditions
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We report an electrochemical protocol for the direct oxidation of internal alkynes in air to provide 1,2-diketones. A variety of functional groups and heterocycle-containing substrates can be tolerated well under mild conditions.
- Zhou, Jie,Tao, Xiang-Zhang,Dai, Jian-Jun,Li, Chen-Guang,Xu, Jun,Xu, Hong-Mei,Xu, Hua-Jian
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supporting information
p. 9208 - 9211
(2019/08/07)
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- Photoinduced Hydroxylation of Organic Halides under Mild Conditions
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Presented in this paper is photoinduced hydroxylation of organic halides, providing a mild access to a range of functionalized phenols and aliphatic alcohols. These reactions generally proceed under mild reaction conditions with no need for a photocatalyst or a strong base and show a wide substrate scope as well as excellent functional group tolerance. This work highlights the unique role of NaI that allows a challenging transformation to proceed under mild reaction conditions.
- Cai, Yue-Ming,Xu, Yu-Ting,Zhang, Xin,Gao, Wen-Xia,Huang, Xiao-Bo,Zhou, Yun-Bing,Liu, Miao-Chang,Wu, Hua-Yue
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p. 8479 - 8484
(2019/10/16)
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- Solid-phase synthesis of biaryl bicyclic peptides containing a 3-aryltyrosine or a 4-arylphenylalanine moiety
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A methodology for the solid-phase synthesis of biaryl bicyclic peptides containing a Phe-Phe, a Phe-Tyr or a Tyr-Tyr motif has been devised. This approach comprises two key steps. The first one involves the cyclization of a linear peptidyl resin containing the corresponding halo- and boronoamino acids via a microwave-assisted Suzuki–Miyaura cross coupling. This step is followed by the macrolactamization of the resulting biaryl monocyclic peptidyl resin leading to the formation of the expected biaryl bicyclic peptide. This study provides the first solid-phase synthesis of this type of bicyclic compounds being amenable to prepare a diversity of synthetic or natural biaryl bicyclic peptides.
- Ng-Choi, Iteng,Oliveras, àngel,Feliu, Lidia,Planas, Marta
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supporting information
p. 761 - 768
(2019/04/17)
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- Preparation method of entresto key intermediate
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The invention relates to the technical field of medicines and particularly relates to a preparation method of a novel entresto key intermediate. When the method provided by the invention is used for preparing the entresto key intermediate, the method is mild in reaction conditions and is green and environmentally friendly; meanwhile, the yield of the method is higher than that of the existing preparation method; the method is economical and effective and is suitable for large-scale industrial production.
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Paragraph 0064; 0065
(2018/03/01)
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- Method for preparing Sacubitril intermediate of anti-heart-failure medicine
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The invention discloses a method for preparing a Sacubitril intermediate of anti-heart-failure medicine as indicated in the formula (VII).The method comprises the following steps of taking D-phenylalanine which is low in price and easy to obtain as the raw material, and conducting an iodination reaction, an esterification reaction, a Boc protection reaction, a negishi coupling reaction, a DIBAL-H reduction reaction and a wittig reaction, so that the Sacubitril intermediate is obtained through preparation.The method for preparing the Sacubitril intermediate is mild in reaction condition and environmentally friendly, compared with existing preparation methods, the yield is higher, and the method is economical, effective and suitable for large-scale industrialized production.
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- Synthesis of Heterocycle-Bridged Peptidic Macrocycles through 1,3-Diyne Transformations
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Macrocyclic tetrapeptide analogues containing a 1,3-diyne moiety were synthesized by a Glaser–Hay-type macrocyclization. The obtained 1,3-diyne was evaluated as a handle to introduce heterocycles into the macrocyclic structure. It was shown that the macrocyclic 1,3-diynes were successfully transformed into various heterocycles by nucleophilic attack of (bis)nucleophiles to the diyne moiety. Treatment with NaHS or H2O as nucleophiles gave rise to 2,5-bridged thiophenes or furans, whereas the use of hydrazines and hydroxylamine gave rise to the corresponding pyrazole- and isoxazole-containing macrocycles. In addition, a thermoreversible Diels–Alder cycloaddition of a cyclopeptidic bridged furan was demonstrated.
- Verlinden, Steven,Ballet, Steven,Verniest, Guido
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supporting information
p. 5807 - 5812
(2016/12/18)
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- Efficient O-Functionalization of Carbohydrates with Electrophilic Reagents
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Novel methodology for O-functionalization of carbohydrate derivatives has been established using bench-stable and easily prepared iodonium(III) reagents. Both electron-withdrawing and electron-donating aryl groups were introduced under ambient conditions and without precautions to exclude air or moisture. Furthermore, the approach was extended both to full arylation of cyclodextrin, and to trifluoroethylation of carbohydrate derivatives. This is the first general approach to introduce traditionally non-electrophilic groups into any of the OH groups around the sugar backbone. The methodology will be useful both in synthetic organic chemistry and biochemistry, as important functional groups can be incorporated under simple and robust reaction conditions in a fast and efficient manner.
- Tolnai, Gergely L.,Nilsson, Ulf J.,Olofsson, Berit
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supporting information
p. 11226 - 11230
(2016/10/13)
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- PROCESSES AND REAGENTS FOR MAKING DIARYLIODONIUM SALTS
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This disclosure relates to processes and reagents for making diaryliodonium salts, which are useful for the preparation of fluorinated, iodinated, astatinated and radiofluorinated aromatic compounds.
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- A universal procedure for the [18F]trifluoromethylation of aryl iodides and aryl boronic acids with highly improved specific activity
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Herein we describe a valuable method for the introduction of the [18F]CF3 group into arenes with highly improved specific activity by the reaction of [18F]trifluoromethane with aryl iodides or aryl boronic acids. This [su
- Vanderborn, Dion,Sewing, Claudia,Herscheid,Windhorst, Albert D.,Orru, Romano V. A.,Vugts, Danielle J.
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p. 11046 - 11050
(2015/03/30)
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- Detection of dihydrofolate reductase conformational change by fret using two fluorescent amino acids
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Two fluorescent amino acids, including the novel fluorescent species 4-biphenyl-l-phenylalanine (1), have been incorporated at positions 17 and 115 of dihydrofolate reductase (DHFR) to enable a study of conformational changes associated with inhibitor binding. Unlike most studies involving fluorescently labeled proteins, the fluorophores were incorporated into the amino acid side chains, and both probes [1 and l-(7-hydroxycoumarin-4-yl)ethylglycine (2)] were smaller than fluorophores typically used for such studies. The DHFR positions were chosen as potentially useful for Foerster resonance energy transfer (FRET) measurements on the basis of their estimated separation (17-18 A) and the expected change in distance along the reaction coordinate. Also of interest was the steric accessibility of the two sites: Glu17 is on the surface of DHFR, while Ile115 is within a folded region of the protein. Modified DHFR I (1 at position 17; 2 at position 115) and DHFR II (2 at position 17; 1 at position 115) were both catalytically competent. However, DHFR II containing the potentially rotatable biphenylphenylalanine moiety at sterically encumbered position 115 was significantly more active than DHFR I. Irradiation of the modified DHFRs at 280 nm effected excitation of 1, energy transfer to 2, and emission by 2 at 450 nm. However, the energy transfer was substantially more efficient in DHFR II. The effect of inhibitor binding was also measured. Trimethoprim mediated concentration-dependent diminution of the emission observed at 450 nm for DHFR II but not for DHFR I. These findings demonstrate that amino acids containing small fluorophores can be introduced into DHFR with minimal disruption of function and in a fashion that enables sensitive monitoring of changes in DHFR conformation.
- Chen, Shengxi,Fahmi, Nour Eddine,Wang, Lin,Bhattacharya, Chandrabali,Benkovic, Stephen J.,Hecht, Sidney M.
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supporting information
p. 12924 - 12927
(2013/09/24)
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- Synthesis and biological evaluation of novel amprenavir-based P1-substituted bi-aryl derivatives as ultra-potent HIV-1 protease inhibitors
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A series of P1-substituted biaryl amprenavir derivatives was designed and synthesized. These compounds were evaluated for enzyme inhibition and antiviral activity in vitro. Several compounds showed highly efficient antiviral activity with EC50 values down to 0.10 nM, which are more potent than marketed HIV-1 protease inhibitors. Docking study indicated that 12c has similar binding mode to amprenavir with full occupancy in P1.
- Yan, Jianwei,Huang, Ning,Li, Shukun,Yang, Liu-Meng,Xing, Weiqiang,Zheng, Yong-Tang,Hu, Youhong
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scheme or table
p. 1976 - 1979
(2012/04/17)
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- Incorporation of phosphole moieties into the side chain of tyrosine and phenylalanine
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A tyrosine derivative with a phosphole moiety covalently attached to the phenolic hydroxy group was successfully prepared through P-O bond-forming reaction, via a nucleophilic substitution reaction at the phosphorus, by slow addition of N-CBz-protected tyrosine methyl ester to a chlorophosphole adduct in the presence of triethylamine, albeit with a low yield. Furthermore, a phenylalanine derivative with a phosphole-containing side chain was conveniently synthesized by Stille cross-coupling reaction of a stannylphosphole reagent with N-Boc-protected 4-iodophenylalanine methyl ester, using Pd(dba)2 as catalyst, in the absence of any additional ligand. These molecules must be seen as valuable building blocks for the preparation of metalloproteins of interest for chemical, biological, and medical applications
- Bisaro, Fabrice,Lefloch, Pascal
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experimental part
p. 3081 - 3085
(2011/02/26)
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- Synthesis and binding studies of two new macrocyclic receptors for the stereoselective recognition of dipeptides
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We present here the design, synthesis, and analysis of a series of receptors for peptide ligands inspired by the hydrogen-bonding pattern of protein β-sheets. The receptors themselves can be regarded as strands 1 and 3 of a three-stranded β-sheet, with crosslinking between the chains through the 4-position of adjacent phenylalanine residues. We also report on the conformational equilibria of these receptors in solution as well as on their tendency to dimerize. 1H NMR titration experiments are used to quantify the dimerization constants, as well as the association constant values of the 1:1 complexes formed between the receptors and a series of diamides and dipeptides. The receptors show moderate levels of selectivity in the molecular recognition of the hydrogen-bonding pattern present in the diamide series, selecting the α-amino acid-related hydrogen-bonding functionality. Only one of the two cyclic receptors shows modest signs of enantioselectivity and moderate diastereoselectivity in the recognition of the enantiomers and diastereoisomers of the Ala-Ala dipeptide (DDG0 1 (DD-DL) = -1.08 kcal/mol and DDG0 1(DD-LD) = -0.89 kcal/mol). Surprisingly, the linear synthetic precursors show higher levels of stereoselectivity than their cyclic counterparts.
- Castilla, Ana Maria,Ballester, Pablo,Conn, M. Morgan
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supporting information; experimental part
(2010/07/18)
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- ARYL AMINO ACID DERIVATIVES AS INHIBITORS FOR TREATING INFLAMMATION
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The present invention relates to a chemical genus of 3-(triaryl)-2-aminopropanol derivative inhibitors of LTA4H (leukotriene A4 hydrolase) useful for the treatment and prevention of inflammatory diseases and disorders. The compounds have general formula III: A particular embodiment is
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Page/Page column 7; 12; 16
(2008/06/13)
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- CYCLIC PEPTIDE ANTITUMOR AGENTS
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Cyclic peptide compounds and derivatives thereof having antitumor activity as shown by treatment of human melanoma, pancreatic, breast, prostate cancer cells.
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Page/Page column 13
(2010/02/11)
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- A new approach for modification of phenylalanine peptides by Suzuki-Miyaura coupling reaction.
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For the first time, we have modified phenylalanine peptides by the Suzuki-Miyaura coupling reaction which may be useful in developing combinatorial libraries of peptidomimetics.
- Kotha,Lahiri
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p. 2887 - 2890
(2007/10/03)
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- BENZAMIDINE DERIVATIVES
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Benzamidine derivatives of the following formulae or analogs thereof, i. e., pharmaceutically acceptable salts thereof, are provided. These compounds or salts thereof have a blood-coagulation inhibiting effect based on an excellent effect of inhibiting the action of activated blood coagulation factor X, and they are useful as anticoagulants.
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- Efficient Synthesis of a Phosphinate Bis-Amino Acid and Its Use in the Construction of Amphiphilic Peptides
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A new amphiphilic bis-amino acid has been designed and its convergent, asymmetric synthesis achieved in differentially protected form.A convenient preparation of iodophenylalanine, a generally useful starting material, is disclosed.Sequential palladium-catalyzed couplings of aryl iodides to phosphinate lead directly to the target protected bis-amino acid.Controlled peptide coupling of the new bis-amino acid is also demonstrated.
- Lei, Haiyan,Stoakes, Mark S.,Herath, Kamal P. B.,Lee, Jinho,Schwabacher, Alan W.
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p. 4206 - 4210
(2007/10/02)
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