- Design, synthesis and evaluation of protein disulfide isomerase inhibitors with nitric oxide releasing activity
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Protein disulfide isomerase (PDI), a chaperone protein mostly in endoplasmic reticulum, catalyzes disulfide bond breakage, formation, and rearrangement to promote protein folding. PDI is regarded as a new target for treatment of several disorders. Here, b
- Li, Lin,Liu, Jian,Ding, Yaqi,Shi, Zhenxiong,Peng, Bo,Yang, Naidi,Hong, Danqi,Zhang, Chengwu,Yao, Chuanhao,Ge, Jingyan,Huang, Wei
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Read Online
- Visible-Light-Induced Oxidative α-Alkylation of Glycine Derivatives with Ethers under Metal-Free Conditions
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In this work, a visible-light-induced oxidative α-alkylation of glycine derivatives with ethers has been developed in the presence of catalytic Eosin Y. Under the blue light of a 3 W LED, a range of α-etherized glycine derivatives, including α-amino esters, α-amino ketones and α-amino amides, were achieved with good to excellent yields and functional group tolerance with tert-butyl hydroperoxide (TBHP) as oxidant at ambient temperature. The operationally easy procedure provides an economical, metal-free, and mild alternative for the synthesis of the α-etherized glycine derivatives.
- Song, Yang,Zhang, Hao,Guo, Jiabao,Shao, Yifei,Ding, Yuzhou,Zhu, Li,Yao, Xiaoquan
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p. 5914 - 5921
(2021/11/22)
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- Fluorescence Detection of Prostate Cancer by an Activatable Fluorescence Probe for PSMA Carboxypeptidase Activity
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Prostate cancer (PCa) is a common malignant tumor among adult males, and convenient intraoperative detection of PCa would reduce the risk of leaving positive surgical margins, especially during nerve-sparing procedures. To achieve rapid, fluorescence-based visualization of PCa, we focused on the glutamate carboxypeptidase (CP) activity of prostate-specific membrane antigen (PSMA), a type II transmembrane glycoprotein that is attracting attention as a PCa biomarker. Based on our finding that aryl glutamate conjugates with an azoformyl linker are recognized by PSMA and have a sufficiently low LUMO (lowest unoccupied molecular orbital) energy level to quench the fluorophore through photoinduced electron transfer, we designed and synthesized a first-in-class activatable fluorescence probe for CP activity of PSMA. The developed probe allowed us to visualize the CP activity of PSMA in living cells and in clinical specimens from PCa patients and is expected to be useful for rapid intraoperative detection and diagnosis of PCa.
- Kawatani, Minoru,Yamamoto, Kyoko,Yamada, Daisuke,Kamiya, Mako,Miyakawa, Jimpei,Miyama, Yu,Kojima, Ryosuke,Morikawa, Teppei,Kume, Haruki,Urano, Yasuteru
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supporting information
p. 10409 - 10416
(2019/07/04)
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- AMINOAMIDE COMPOUNDS
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Compounds with amino amide linkers and pharmaceutical compositions and medicaments comprising such compounds are disclosed. The compounds modulate protein function of 1L-1β, IL-2, IL-6, TNF-α, CK1α, GSPT1, aiolos, ikaros or helios, or combinations thereof. In addition, methods of making such compounds and their uses for treating or ameliorating diseases, disorders, or conditions associated with protein malfunction, such as cancer, are provided.
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Paragraph 0166
(2020/01/08)
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- Transition-Metal-Free N-Arylation of Amines by Triarylsulfonium Triflates
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A simple and efficient method for transition-metal-free N-arylation of various amines by triarylsulfonium triflates is described. Both aliphatic and aromatic amines were smoothly converted at 80 °C in the presence of tBuOK or KOH to give the corresponding mono N-arylated products in good to high yields. The molar ratios of the reactants and the choice of bases had a big effect on the reaction. When a large excess of [Ph3S][OTf] and tBuOK were employed for primary amines under the standard conditions, the bis(N-phenyl) products were predominantly formed. This method was also applicable to the synthesis of bioactive N-phenyl amino acid derivatives. The control experiments, the deuterium labelling study, and the presence of regioisomers of N-arylated products when using 4-substituted triarylsulfonium triflates suggested that the reaction might proceed through an aryne intermediate. The present protocol demonstrated that triarylsulfonium salts are versatile arylation reagents in the construction of CAr?N bonds.
- Tian, Ze-Yu,Ming, Xiao-Xia,Teng, Han-Bing,Hu, Yu-Tian,Zhang, Cheng-Pan
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supporting information
p. 13744 - 13748
(2018/09/14)
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- Reagent-free continuous thermal tert-butyl ester deprotection
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Continuous processing enables the use of non-standard reaction conditions such as high temperatures and pressures while in the liquid phase. This expands the chemist's toolbox and can enable previously unthinkable chemistry to proceed with ease. For a series of amphoteric amino acid derivatives, we have demonstrated the ability to hydrolyze the tert-butyl ester functionality in protic solvent systems. Using a continuous plug flow reactor at 120–240 °C and 15–40 min reaction times, no pH modification or additional reagents are needed to achieve the desired transformation. The method was then expanded to encompass a variety of more challenging substrates to test selectivity and racemization potential. The acid products were generally isolated as crystalline solids by simple solvent exchange after the deprotection reaction in good to high yield and purity.
- Cole, Kevin P.,Ryan, Sarah J.,Groh, Jennifer McClary,Miller, Richard D.
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p. 6209 - 6217
(2017/09/30)
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- Development of a Method for the N-Arylation of Amino Acid Esters with Aryl Triflates
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A general method for the N-arylation of amino acid esters with aryl triflates is described. Both α- and β-amino acid esters, including methyl, tert-butyl, and benzyl esters, are viable substrates. Reaction optimization was carried out by design of experim
- King, Sandra M.,Buchwald, Stephen L.
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supporting information
p. 4128 - 4131
(2016/08/30)
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- MYOGLOBIN-BASED CATALYSTS FOR CARBENE TRANSFER REACTIONS
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Methods are provided for carrying out carbene transfer transformations such as olefin cyclopropanation reactions, carbene heteroatom-H insertion reactions (heteroatom = N, S, Si), sigmatropic rearrangement reactions, and aldehyde olefination reactions with high efficiency and selectivity by using a novel class of myoglobin-based biocatalysts. These methods are useful for the synthesis of a variety of organic compounds which contain one or more new carbon-carbon or carbon-heteroatom (N, S, or Si) bond. The methods can be applied for conducting these transformations in vitro (i.e., using the biocatalyst in isolated form) and in vivo (i.e., using the biocatalyst in a whole cell system).
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Paragraph 00278; 00279; 00291
(2016/06/14)
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- Myoglobin-catalyzed intermolecular carbene N-H insertion with arylamine substrates
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Engineered variants of the heme-containing protein myoglobin can efficiently catalyze the insertion of α-diazo esters into the N-H bond of arylamines, featuring a combination of high chemoselectivity, elevated turnover numbers, and broad substrate scope.
- Sreenilayam, Gopeekrishnan,Fasan, Rudi
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supporting information
p. 1532 - 1534
(2015/08/03)
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- The tert-butyl side chain: A powerful means to lock peptoid amide bonds in the cis conformation
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The very simple sterically hindered tert-butyl side chain exerts complete control over the peptoid amide geometry which only exists in the cis conformation. It is exemplified in NtBu glycine homo-oligomers and in linear oligopeptoids designed with an alte
- Roy,Caumes,Esvan,Didierjean,Faure,Taillefumier
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supporting information
p. 2246 - 2249
(2013/06/05)
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- Peptoid atropisomers
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We report the isolation of N-aryl peptoid oligomers that adopt chiral folds, despite the absence of chiral centers. Peptoid monomers incorporating ortho-substituted N-aryl side chains are identified that exhibit axial chirality. We observe significant ene
- Paul, Bishwajit,Butterfoss, Glenn L.,Boswell, Mikki G.,Renfrew, P. Douglas,Yeung, Fanny G.,Shah, Neel H.,Wolf, Christian,Bonneau, Richard,Kirshenbaum, Kent
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supporting information; experimental part
p. 10910 - 10919
(2011/09/30)
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- Rhodium(NHC)-catalyzed amination of aryl bromides
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(Figure Presented) A rhodium-catalyzed amination reaction of aryl halides with amines has been developed with the use of a N-heterocyclic carbene (NHC) ligand (I/Pr = 1,3-diisopropylimidazol-2-ylidene). The active metal species responsible for the reaction progress was identified. The developed procedure of the Rh-catalyzedW-arylation is convenient to carry out under mild reaction conditions displaying a wide range of substrate scope and high degree of functional group tolerance.
- Kim, Min,Chang, Sukbok
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supporting information; experimental part
p. 1640 - 1643
(2010/06/16)
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- Copper-catalyzed enantioselective propargylic amination of propargylic esters with amines: Copper-allenylidene complexes as key intermediates
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The scope and limitations of the copper-catalyzed propargylic amination of various propargylic esters with amines are presented, where optically active diphosphines such as Cl-MeO-BIPHEP and BINAP work as good chiral ligands. A variety of secondary amines are available as nucleophiles for this catalytic reaction to give the corresponding propargylic amines with a high enantioselectivity. The results of some stoichiometric and catalytic reactions indicate that the catalytic amination proceeds via copper-allenylidene complexes formed in situ, where the attack of amines to the electrophilic γ-carbon atom in the allenylidene complex is an important step for the stereoselection. Investigation of the relative rate constants for the reaction of several para-substituted propargylic acetates with N-methylanilines reveals that the formation of the copper-allenylidene complexes is involved in the rate-determining step. The result of the density functional theory calculation on a model reaction also supports the proposed reaction pathway involving copper-allenylidene complexes as key intermediates. The catalytic procedure presented here provides a versatile and direct method for the preparation of a variety of chiral propargylic amines.
- Hattori, Gaku,Sakata, Ken,Matsuzawa, Hiroshi,Tanabe, Yoshiaki,Miyake, Yoshihiro,Nishibayashi, Yoshiaki
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supporting information; experimental part
p. 10592 - 10608
(2010/09/10)
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- Selective urokinase-type plasminogen activator inhibitors. 4. 1-(7-Sulfonamidoisoquinolinyl)guanidines
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1-Isoquinolinylguanidines were previously disclosed as potent and selective inhibitors of urokinase-type plasminogen activator (uPA). Further investigation of this template has revealed that incorporation of a 7-sulfonamide group furnishes a new series of potent and highly selective uPA inhibitors. Potency and selectivity can be achieved with sulfonamides derived from a variety of amines and is further enhanced by the incorporation of sulfonamides derived from amino acids. The binding mode of these 1-isoquinolinylguanidines has been investigated by X-ray cocrystallization studies. uPA inhibitor 26 was selected for further evaluation based on its excellent enzyme potency (Ki 10 nM) and selectivity profile (4000-fold versus tPA and 2700-fold versus plasmin). In vitro, compound 26 is able to inhibit exogenous uPA in human chronic wound fluid (IC50 = 0.89 μM). In vivo, in a porcine acute excisional wound model, following topical delivery, compound 26 is able to penetrate into pig wounds and inhibit exogenous uPA activity with no adverse effect on wound healing parameters. On the basis of this profile, compound 26 (UK-371,804) was selected as a candidate for further preclinical evaluation for the treatment of chronic dermal ulcers.
- Fish, Paul V.,Barber, Christopher G.,Brown, David G.,Butt, Richard,Collis, Michael G.,Dickinson, Roger P.,Henry, Brian T.,Horne, Valerie A.,Huggins, John P.,King, Elizabeth,O'Gara, Margaret,McCleverty, Dawn,McIntosh, Fraser,Phillips, Christopher,Webster, Robert
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p. 2341 - 2351
(2008/02/03)
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- 3-CARBOXY PYRROLES AS ANTI-VIRAL AGENTS
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Novel antiviral compounds of Formula (I) : wherein: A represents hydroxy; R4 represents hydrogen and the other substituents are as defined in the claims; and salts, solvates and esters thereof; processes for their preparation, pharmaceutical co
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Page/Page column 18
(2010/11/24)
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- Composition for the treatment of damaged tissue
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A pharmaceutical for use in damaged tissue, such as wound, treatment (e.g. healing) is described. The pharmaceutical comprising a composition which comprises: (a) a growth factor; and (b) an inhibitor agent; and optionally (c) a pharmaceutically acceptable carrier, diluent or excipient; wherein the inhibitor agent can inhibit the action of at least one specific adverse protein (e.g. a specific protease) that is upregulated in a damaged tissue, such as a wound, environment.
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- N-phenyl-N-acetamidoglycinamides, their preparation and medicaments containing them
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Compounds of formula: STR1 in which R1 represents a hydrogen atom or an alkyl, alkoxycarbonyl or an unsubstituted or substituted phenyl radical, R2 represents a hydrogen atom or an unsubstituted or substituted alkyl radical, R3 represents an alkyl, phenylalkyl, indanyl, cycloalkylalkyl or an unsubstituted or substituted phenyl radical, or R2 and R3 form a heterocycle together with the nitrogen atom to which they are attached, and R4 represents an unsubstituted or substituted phenyl radical, a naphthyl, indolyl or quinolyl radical or a phenylamino radical in which the phenyl ring is unsubstituted or substituted, their preparation and medicaments containing them.
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- Hexapeptide anaphylatoxin-receptor ligands
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Oligopeptide compounds or oligopeptide analogue compounds of the formula A-B-D-E-G-J-L-M-Q are ligands for the anaphylatoxin receptor and are useful in the treatment of inflammatory disease states.Also disclosed are anaphylatoxin receptor ligand compositi
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- N-phenyl-n-alkoxycarbonylalkyl glycinamides, their preparation and the medicaments containing them
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This invention relates to compounds of formula: STR1 in which R1 represents a hydrogen atom or an alkyl or alkoxycarbonyl radical or an unsubstituted or substituted phenyl radical, R2 represents an alkyl (1-8 C) or polyfluoroalkyl ra
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- Angiotensin-Converting Enzyme Inhibitors. New Orally Active Antihypertensive (Mercaptoalkanoyl)- and glycine Derivatives
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A variety of N-substituted (mercaptoalkanoyl)- and glycine derivatives was synthesized and their ability in inhibiting the activity of angiotensin-converting enzyme (ACE) was examined in vitro and in vivo.The acylthio derivatives prepared are assumed to act as prodrugs since they are much less active than the corresponding free SH compounds in vitro and can be expected to act in vivo only after conversion to the free sulfhydryl compounds.A number of this compounds are potent ACE inhibitors that lowered blood pressure in Na-deficient, conscious spontaneously hypertensive rats (SHR), a high renin model.One of the most active members of the series was (S)-N-cyclopentyl-N--2-methyl-1-oxopropyl>glycine (REV 3659-(S), pivopril).Structure-activity relationships are discussed.
- Suh, John T.,Skiles, Jerry W.,Williams, Bruce E.,Youssefyeh, Raymond D.,Jones, Howard,et al.
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