- Examination of N-hydroxylation as a prerequisite mechanism of nitric oxide synthase inactivation
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L-N5-(1-Hydroxyiminoethyl)-ornithine (L-NHIO) and L-N6-(1-hydroxyiminoethyl)-lysine (L-NHIL) were synthesized and tested as potential intermediates in the mechanism-based inactivation of nitric oxide synthase (NOS) by L-N5-iminoethyl-ornithine (L-NIO) and L-N6-iminoethyllysine (L-NIL). Although these compounds were determined to be competitive inhibitors, mechanism-based inactivation was not observed. (C) 2000 Elsevier Science Ltd. All rights reserved.
- Maurer, Tristan S.,Pan, Jianping,Booth, Brian P.,Kalman, Thomas I.,Fung, Ho-Leung
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Read Online
- An affinity-based probe for the proteomic profiling of aspartic proteases
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We have developed an affinity-based probe for the proteomic profiling of aspartic proteases. Our probe was shown to be selective towards aspartic proteases over other proteins. It was also shown that the strategy may be used to label selectively aspartic proteases in the presence of a large excess of other proteins, thus making it useful for future proteome profiling experiments.
- Chattopadhaya, Souvik,Chan, Elaine W. S.,Yao, Shao Q.
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Read Online
- The microenvironment and pKaperturbation of aminoacyl-tRNA guided the selection of cationic amino acids
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The proteinogenic lysine (Lys) and arginine (Arg) have multiple methylene groups between α-carbon and the terminal charged centre. Why nature did not select ornithine (Orn), 2,4-diamino butyric acid (Dab) and 2,3-diamino propionic acid (Dpr) with fewer methylene groups in the side chain remains an important question! The propensity of aminoacyl-tRNA (aa-tRNA) model substrates towards self-degradationviaintramolecular lactamization was studied using UV spectroscopy and1H-NMR titration, which showed that Lys and Arg remain stable, and Orn and Dab cyclize to lactam. Hydrophobicity-assisted surface mediated model peptide formation highlighted that the microenvironment and pKaperturbation led to poor regioselectivity (α-aminevs.terminal amine) in Dpr and other non-proteinogenic analogues. The α-selectivity became even poorer in the presence of phosphate, making them ill-suited for peptide synthesis. Superior regioselectivity of the Lys aa-tRNA model substrate suggests that the extra methylene bridge helped nature to separate the microenvironments of the α-amine and ε-amine to synthesize the peptide backbone.
- Hazra, Bibhas,Prasad, Mahesh,Roy, Rajat,Tarafdar, Pradip K.
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supporting information
p. 8049 - 8056
(2021/10/04)
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- COMPOUND COMPRISING A NUCLEIC ACID AND A HALF-LIFE EXTENSION MOTIF
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Disclosed herein are compounds including a nucleic acid (A), their preparation, and their use.
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Paragraph 0758
(2021/06/04)
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- A GENETICALLY ENCODED, PHAGE-DISPLAYED CYCLIC PEPTIDE LIBRARY AND METHODS OF MAKING THE SAME
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Embodiments of the present disclosure pertain to methods of selecting cyclic peptides that bind to a target by transforming a phage display library with a plurality of nucleic acids into bacterial host cells, where the nucleic acids include phage coat protein genes with a combinatorial region that encodes at least one cysteine and at least one non-canonical amino acid. The transformation results in the production of phage particles with phage coat proteins where the cysteine and the non-canonical amino acid couple to one another to form a cyclic peptide library. Phage particles are then screened against the desired target to select bound cyclic peptides. Amino acid sequences of the selected cyclic peptides are then identified. Additional embodiments pertain to methods of constructing a phage display library that encodes the cyclic peptides. Further embodiments of the present disclosure pertain to the produced cyclic peptides, phage display libraries and phage particles.
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Paragraph 0094; 00111; 00172-00173
(2020/12/07)
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- Two Distinct Mechanisms for C-C Desaturation by Iron(II)- and 2-(Oxo)glutarate-Dependent Oxygenases: Importance of α-Heteroatom Assistance
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Hydroxylation of aliphatic carbons by nonheme Fe(IV)-oxo (ferryl) complexes proceeds by hydrogen-atom (H?) transfer (HAT) to the ferryl and subsequent coupling between the carbon radical and Fe(III)-coordinated oxygen (termed rebound). Enzymes that use H?-abstracting ferryl complexes for other transformations must either suppress rebound or further process hydroxylated intermediates. For olefin-installing C-C desaturations, it has been proposed that a second HAT to the Fe(III)-OH complex from the carbon α to the radical preempts rebound. Deuterium (2H) at the second site should slow this step, potentially making rebound competitive. Desaturations mediated by two related l-arginine-modifying iron(II)- and 2-(oxo)glutarate-dependent (Fe/2OG) oxygenases behave oppositely in this key test, implicating different mechanisms. NapI, the l-Arg 4,5-desaturase from the naphthyridinomycin biosynthetic pathway, abstracts H? first from C5 but hydroxylates this site (leading to guanidine release) to the same modest extent whether C4 harbors 1H or 2H. By contrast, an unexpected 3,4-desaturation of l-homoarginine (l-hArg) by VioC, the l-Arg 3-hydroxylase from the viomycin biosynthetic pathway, is markedly disfavored relative to C4 hydroxylation when C3 (the second hydrogen donor) harbors 2H. Anchimeric assistance by N6 permits removal of the C4-H as a proton in the NapI reaction, but, with no such assistance possible in the VioC desaturation, a second HAT step (from C3) is required. The close proximity (≤3.5 ?) of both l-hArg carbons to the oxygen ligand in an X-ray crystal structure of VioC harboring a vanadium-based ferryl mimic supports and rationalizes the sequential-HAT mechanism. The results suggest that, although the sequential-HAT mechanism is feasible, its geometric requirements may make competing hydroxylation unavoidable, thus explaining the presence of α-heteroatoms in nearly all native substrates for Fe/2OG desaturases.
- Dunham, Noah P.,Chang, Wei-Chen,Mitchell, Andrew J.,Martinie, Ryan J.,Zhang, Bo,Bergman, Jonathan A.,Rajakovich, Lauren J.,Wang, Bo,Silakov, Alexey,Krebs, Carsten,Boal, Amie K.,Bollinger, J. Martin
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supporting information
p. 7116 - 7126
(2018/05/15)
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- An Allyl Protection and Improved Purification Strategy Enables the Synthesis of Functionalized Phosphonamidate Peptides
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For modern biophysical methods such as isothermal titration calorimetry, high purity of the inhibitor of interest is indispensable. Herein, we describe a procedure for the synthesis and purification of functionalized phosphonamidate peptides that is able to generate inhibitors for the metalloprotease thermolysin for use in biophysical experiments. The method utilizes an allyl ester/alloc protection strategy and takes advantage of a fast and effective solid-phase extraction (SPE) purification step. Applying this strategy, we were able to synthesize a series of highly polar inhibitors featuring amino- and hydroxy-functionalized side chains in excellent purity.
- Cramer, Jonathan,Klebe, Gerhard
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supporting information
p. 1857 - 1866
(2017/04/06)
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- Paliperidone amino acid ester and its preparation method
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The invention discloses a preparation method of a paliperidone amino-acid ester compound or medicinal salt thereof used for treating mental disease, wherein the structural formula of the compound is shown as a formula (I) (described in the specification). The compound can be an optical isomer and also can be a racemic mixture. The paliperidone amino-acid ester can be metabolized and converted into paliperidone (II) with pharmacological activity in vivo after being ingested in a human body, the paliperidone (II) is taken as an antagonist for neurotransmission substance to play a pesticide effect, and the paliperidone (II) is used for treating related mental diseases such as schizophrenia.
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Paragraph 0050; 0051; 0052
(2017/01/12)
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- A kind of amino acid- the amine decorates composition and its preparation method and application
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The invention belongs to the field of medicinal chemistry and in particular relates to amino acid-amine conjugate and a preparation method and application thereof. A general formula of the amino acid-amine conjugate is shown in the specification. According to the amino acid-amine conjugate, amino acid and amine are combined together, the water solubility, biological properties and drug targeting of amine compounds can be improved, and anti-cancer targeting can be realized.
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Paragraph 0058; 0059; 0062
(2017/04/05)
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- A diversity-oriented synthesis strategy enabling the combinatorial-type variation of macrocyclic peptidomimetic scaffolds
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Macrocyclic peptidomimetics are associated with a broad range of biological activities. However, despite such potentially valuable properties, the macrocyclic peptidomimetic structural class is generally considered as being poorly explored within drug discovery. This has been attributed to the lack of general methods for producing collections of macrocyclic peptidomimetics with high levels of structural, and thus shape, diversity. In particular, there is a lack of scaffold diversity in current macrocyclic peptidomimetic libraries; indeed, the efficient construction of diverse molecular scaffolds presents a formidable general challenge to the synthetic chemist. Herein we describe a new, advanced strategy for the diversity-oriented synthesis (DOS) of macrocyclic peptidomimetics that enables the combinatorial variation of molecular scaffolds (core macrocyclic ring architectures). The generality and robustness of this DOS strategy is demonstrated by the step-efficient synthesis of a structurally diverse library of over 200 macrocyclic peptidomimetic compounds, each based around a distinct molecular scaffold and isolated in milligram quantities, from readily available building-blocks. To the best of our knowledge this represents an unprecedented level of scaffold diversity in a synthetically derived library of macrocyclic peptidomimetics. Cheminformatic analysis indicated that the library compounds access regions of chemical space that are distinct from those addressed by top-selling brand-name drugs and macrocyclic natural products, illustrating the value of our DOS approach to sample regions of chemical space underexploited in current drug discovery efforts. An analysis of three-dimensional molecular shapes illustrated that the DOS library has a relatively high level of shape diversity.
- Isidro-Llobet, Albert,Hadje Georgiou, Kathy,Galloway, Warren R. J. D.,Giacomini, Elisa,Hansen, Mette R.,Méndez-Abt, Gabriela,Tan, Yaw Sing,Carro, Laura,Sore, Hannah F.,Spring, David R.
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supporting information
p. 4570 - 4580
(2015/04/14)
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- Genetically encoded unstrained olefins for live cell labeling with tetrazine dyes
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A number of non-canonical amino acids (NCAAs) with unstrained olefins are genetically encoded using mutant pyrrolysyl-tRNA synthetase-tRNAPylCUA pairs. These NCAAs readily undergo inverse electron-demand Diels-Alder cycloadditions with tetrazine dyes, leading to selective labeling of proteins bearing these NCAAs in live cells. This journal is
- Lee, Yan-Jiun,Kurra, Yadagiri,Yang, Yanyan,Torres-Kolbus, Jessica,Deiters, Alexander,Liu, Wenshe R.
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supporting information
p. 13085 - 13088
(2015/02/19)
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- A study on effects of naphthalimide derivative-capped quantum dots on the cellular internalization, proliferation, and apoptosis ability
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Quantum dots (QDs) have shown great potential in monitoring and imaging cancer cells because of their unique photochemical and photophysical properties. However, it is little-known whether QDs affect the cellular internalization, proliferation and apoptosis. Here a new class of multifunctional QDs capped with ligands that possess l-Lys or l-Arg and naphthalimide (NI), linked by carboxyl groups (l-Lys-NI@QDs and l-Arg-NI@QDs, respectively), have been synthesized. We found that these QDs are of controllable sizes, in the range of 4 to 5 nm and have strong optical emission properties. The cellular uptake of NI derivative-capped QDs was monitored by flow cytometry and confocal microscopy. The results of in vitro cytotoxicity revealed that NI derivative-capped QDs, with better cell selectivity, could inhibit the growth of multiple cancer cells more potently than amonafide. They effectively inhibited the proliferation of cells due to apoptosis, which was confirmed by Hoechst 33342, annexin V-FITC and JC-1 staining and mitochondrial membrane potential (MMP) experiments. The most potent NI derivative-capped QDs, l-Arg-NI@CdSe/ZnS, were verified to efficiently induce apoptosis via a reactive oxygen species (ROS) mediating mitochondrial dysfunction, and were more effective in promoting programmed cell death in HepG2 cells in a preliminary mechanistic study. This journal is
- Zhao, Mei-Xia,Zeng, Er-Zao,Li, Yang,Wang, Chao-Jie
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p. 7351 - 7359
(2015/02/19)
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- Design, synthesis and primary activity of thiomorpholine derivatives as DPP-IV inhibitors
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Thirteen thiomorpholine-bearing compounds were designed and synthesized as dipeptidyl peptidase IV (DPP-IV) inhibitors, with natural and non-natural l-amino acids as the starting materials. Their structures were characterized by 1H NMR, 13C NMR and HR-MS. The target compounds were screened for the DPP-IV inhibition, and the preliminary SAR result was obtained. Particularly, compounds 4c, 4d and 4f with good DPP-IV inhibition in vitro were further evaluated through a mouse oral glucose tolerance test (OGTT). The preliminary result showed the potential value for further studies on those thiomorpholine-bearing compounds as DPP-IV inhibitors.
- Han, Bei,Liu, Jing Long,Huan, Yi,Li, Peng,Wu, Qi,Lin, Zi Yun,Shen, Zhu Fang,Yin, Da Li,Huang, Hai Hong
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scheme or table
p. 297 - 300
(2012/05/20)
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- Inhibitors selective for HDAC6 in enzymes and cells
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Histone deacetylase inhibitors with anticancer or anti-inflammatory activity bind to Class I or Class I and II HDAC enzymes. Here we compare selectivity of inhibitors of a Class II HDAC enzyme (HDAC6) and find one that retains high selectivity in macrophages.
- Gupta, Praveer K.,Reid, Robert C.,Liu, Ligong,Lucke, Andrew J.,Broomfield, Steve A.,Andrews, Melanie R.,Sweet, Matthew J.,Fairlie, David P.
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supporting information; experimental part
p. 7067 - 7070
(2011/01/03)
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- PROCESS FOR THE PREPARATION OF ε-ALKOXYCARBONYLLYSINES AND THEIR ANALOGUES
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A process for the preparation of ω-alkoxycarbonylamino-α-aminoacids and α,ω orthogonally diprotected diaminoacids from α,ω-diaminoacids using 1- alkoxycarbonylbenzotriazoles as protecting agents is disclosed. In an alternative embodiment, carbamoylating agents in the presence of benzotriazoles are used instead of 1-alkoxycarbonylbenzotriazoles. This reaction is preferably applied to the preparation of ε- alkoxycarbonyllysines from lysine. A process for the preparation of t-butoxycarbonylbenzotriazoles and novel complexes of ω-alkoxycarbonylamino-α-aminoacids with benzotriazoles are also disclosed.
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Page/Page column 13-14
(2008/06/13)
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- D-amino acid specific proteases and native all-L-proteins: A convenient combination for semisynthesis
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(Figure Presented) Side reactions side-stepped: A D-amino acid specific protease was used for the first time in the chemoenzymatic synthesis of a native protein, the peptidyl prolyl cis/trans isomerase parvulin 10 from E. coli (see scheme). Side reactions that complicate synthesis with L-amino acid specific enzymes are avoided in this approach.
- Wehofsky, Nicole,Pech, Andreas,Liebscher, Sandra,Schmidt, Stephanie,Komeda, Hidenobu,Asano, Yasuhisa,Bordusa, Frank
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supporting information; experimental part
p. 5456 - 5460
(2009/03/12)
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- Magnesium/hydrazinium monoformate: A new hydrogenation method for removal of some commonly used protecting groups in peptide synthesis
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Removal of some commonly used protecting groups in peptide synthesis by catalytic transfer hydrogenation employing hydrazinium monoformate and magnesium is described. This method is equally competitive with other methods in deblocking most of the commonly used protecting groups in peptide synthesis. tert-Butyl derived and base labile protecting groups were completely stable under these conditions. The use of Mg/NH2-NH2·HCOOH makes this a rapid, low-cost alternative to palladium and reduces the work-up to a simple and extraction operation.
- Channe Gowda
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p. 311 - 313
(2007/10/03)
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- Synthesis of dye-labeled lysine derivatives
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The N(ε)-dabcyl-N(α)-(9-fluorenylmethoxy)-carbonyllysine was prepared by reaction of lysine-Cu2+ complex with the N-hydroxysuccinimide (HOSu) activated ester of [4-(4'-dimethylamino)phenylazo]benzoic acid (dabcyl acid) followed by treatment with EDTA and acylation with Fmoc-OSu, and the N(α)tert-butyloxycarbonyl-N(ε)-dabcyllysine was prepared by reaction of N(α)-tertbutyloxycarbonyllysine with dabcyl-OSu.
- Shen, Zongxuan,Zhang, Yawen,Chen, Yan
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p. 2525 - 2532
(2007/10/03)
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- Ammonium formate catalytic transfer hydrogenation: A convenient method for removal of halogenated benzyloxycarbonyl and benzyl protecting groups in peptide synthesis
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A new application of ammonium formate catalytic transfer hydrogenolysis, in the presence of palladised carbon, for removal of 2-chlorobenzyloxycarbonyl (2-ClZ), 2,6-dichlorobenzyl (2,6-Cl2Bzl), bromobenzyloxycarbonyl (BrZ) and phenacyl ester (OPa) from amino acids, peptides and high molecular weight polymers is reported.
- Gowda,Rajesh,Gowda
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p. 504 - 508
(2007/10/03)
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- Selective deprotection of phenacyl, benzyl and methyl esters of N-protected amino acids and dipeptides and N-protected amino acids benzyl ester linked to resins with bis(tributyltin) oxide
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Phenacyl, methyl and benzyl esters of various N-α-Boc, N-α-Cbz or N,N-dimethylamino protected amino acids and dipeptides, as well as esters of N-α-protected amino acids linked to Wang and Pam resins have been efficiently and chemoselectively cleaved by bis(tributyltin) oxide in aprotic solvents to give the corresponding carboxylic acids in good yields. Moreover, the absence of racemization during the deprotection has been demonstrated. A limitation of the method is the instability of the N-ε-Fmoc group in the amino acid esters 8 and 10, N-α-Fmoc-L-alanine linked to Wang resin 23 and the Cbz protecting groups in N-α-Boc-N-ε-Cbz-L-lysine benzyl and methyl esters (5 and 7), respectively, and N-α-Cbz-L-alanyl-L-alanine methyl ester 19. In the case of N-α-protected dipeptides, there was no evidence of free amino acid which indicates that the peptide bond is unaffected.
- Salomon, Claudio J.,Mata, Ernesto G.,Mascaretti, Oreste A.
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p. 995 - 999
(2007/10/03)
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- A highly efficient method of N-methylation for the amino acid derivatives
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Many naturally occurring, biologically active cyclic peptides are found to contain several N-methyl amino acid constituents.A method has been found out for the N-methylation of amino acid derivatives using sodium hexamethyl disilazide and methyl iodide which gives very good yield without the racemisation.
- Belagali, Shiddappa L.,Mathew, Thankamma,Himaja, M.,Kocienski, Philip
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- Reversible protection of lysine to facilitate the purification of protected peptide segments
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The polarity of temporarily free lysine side chains can be exploited to aid in the purification of protected peptides. The amine groups can easily be reprotected after the purification step. Impurities in commercial TFE1 can cause trifluoroacetylation of free primary amines.
- Rizo, Josep,Albericio, Fernando,Giralt, Ernest,Pedroso, Enrique
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p. 397 - 400
(2007/10/02)
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- Synthesis of Unnatural Amino Acids
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This communication presents efficient synthetic procedures for the D and L isomers of Nα-tert-butyloxycarbonyl-Nε-benzyloxycarbonyl-Nε-isopropyllysine dicyclohexylamine salt (Nα-Boc-Nε-Z-Ilys DCHA salt), the D and L isomers of Nα-tert-butyloxycarbonyl-Nεnicotinoyllysine (Nα-Boc-Niclys), β-(3-quinolyl)-D,L-alanine (3-Quinal), and the resolution into the D and L isomers of 3-Quinal.
- Acosta, C. Kirk,Bahr, Martin L.,Burdett, James E.,Cessac, James W.,Martinez, Rudy A.,et al.
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p. 914 - 934
(2007/10/02)
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- PALLADIUM-CATALYZED REACTION OF TRIBUTYLTIN HYDRIDE. SELECTIVE AND VERY MILD DEPROTECTION OF ALLYL AND ALLYLOXYCARBONYL DERIVATIVES OF AMINO-ACIDS.
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Allyl(All) and Allyloxycarbonyl(Alloc) amino-acid derivatives are deprotected through palladium-catalyzed hydrostannolysis by Bu3SnH in a highly selective manner.Benzyl and benzyloxycarbonyl groups are stable under these conditions.Moreover the allyl and Alloc groups seem orthogonal to the t-butyl and t-butoxycarbonyl protecting groups.
- Guibe, F.,Dangles, O.,Balavoine, G.
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p. 2365 - 2368
(2007/10/02)
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- Selective Removal of Electron-Accepting p-Toluene- and Naphthalenesulfonyl Protecting Groups for Amino Function via Photoinduced Donor-Acceptor Ion Pairs with Electron-Donating Aromatics
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When N-tosylamines (3a, 3b, 7, 17a, 17b, 21, 23) in aqueous ethanol were irradiated with a high-pressure mercury lamp in the presence of an electron-donating aromatic such as 1,2- (6) and 1,4-dimethoxybenzenes (10) and 1,5-dimethoxynaphthalene (14) and a reductant (sodium borohydride, ascorbic acid, ammonia borane, hydrazine), a photochemical detosylation proceeded quite easily to give the corresponding amines (4a, 4b, 8, 18a, 18b, 22, 24) in the high yields.On irradiation in the presence of 10 and sodium borohydride, N-(naphthalenesulfonyl)phenethylamine (19) also gave 4a.Mechanistic studies based on fluorescence quenching, quantum yield measurement, and free energy change calculation show that this photoreaction involves an electron transfer from an electron-donating aromatic to an electron-accepting sulfonamide.A preliminary application for the synthesis of lysine peptides was also described.
- Hamada, Tatsuo,Nishida, Atsushi,Yonemitsu, Osamu
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p. 140 - 145
(2007/10/02)
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- CLEAVAGE OF PEPTIDE TO SPARROW-RESIN BOND BY CATALYTIC TRANSFER HYDROGENOLYSIS WITH 1,4-CYCLOHEXADIENE
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Cleavage of benzyl ester-type linkage to the Sparrow modified polystyrene support was attempted with the aid of catalytic transfer hydrogenation using 1,4-cyclohexadiene and palladium black, and satisfactory yields were obtained.This will provide an alternatively efficient and mild method for the final deblocking step during improved solid phase peptide synthesis.
- Colombo, Roberto
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p. 1119 - 1122
(2007/10/02)
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