- Allylpalladium(II) histidylidene complexes and their application in Z-selective transfer semihydrogenation of alkynes
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We have studied the use of amino acid histidine as a precursor for N-heterocyclic carbene (NHC) ligands. This natural amino acid possesses an imidazole substituent, which makes it an interesting NHC precursor that contains both an acid and an amino functi
- Drost, Ruben M.,Broere, Dani?l L. J.,Hoogenboom, Jorin,De Baan, Simone N.,Lutz, Martin,De Bruin,Elsevier
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Read Online
- Total Synthesis and Functional Characterization of Selenoneine
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The N-α-trimethyl 2-selenohistidine selenoneine is the selenium isolog of the natural antioxidant ergothioneine. Sulfur-to-selenium substitutions are known to endow proteins and nucleic acids with special activities. In contrast, secondary metabolites tha
- Lim, David,Gründemann, Dirk,Seebeck, Florian P.
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Read Online
- Development of targeted nanoparticles loaded with antiviral drugs for SARS-CoV-2 inhibition
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Recently, a novel coronavirus, known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has raised global concerns, being the etiological agent of the current pandemic infectious coronavirus disease 2019 (COVID-19). Specific prophylactic treatments like vaccines, have been authorized for use by regulatory bodies in multiple countries, however there is an urgent need to identify new, safe, and targeted therapeutics as post-exposure therapy for COVID-19. Among a plethora of potential pharmacological targets, the angiotensin-converting enzyme 2 (ACE2) membrane receptor, which plays a crucial role in viral entry, is representing an attractive intervention opportunity for SARS-CoV-2 antiviral discovery process. In this scenario, we envisioned that binding to ACE2 by multivalent attachment of ligands to nanocarriers incorporating antiviral therapeutics, it would increase receptor avidity and impart specificity to these nanovectors for host cells, particularly in the pulmonary tract, which is the primary entry route for SARS-CoV-2. Herein, we report the design and development of novel polymeric nanoparticles (NP), densely grafted with various ligands to selectively bind to ACE2, as innovative nanovectors for targeted drug delivery. We first evaluated the impact of these biocompatible targeted NP (TNP) on ligand binding toward ACE2 and measured their competition ability vs a model of spike protein (Lipo-S1). Next, we tested the effectiveness of the most performing nanoprotopype, TNP-1, loaded with a model anti-SARS-CoV-2 drug such as remdesivir (RDV), on antiviral activity against SARS-CoV-2 infected Vero E6 cells. The RDV-TNP-1 exhibited a significantly improved antiviral effect compared to RDV at the same concentration. Interestingly, unloaded TNP (TNP-1E) also exhibited a basal antiviral activity, potentially due to a direct competitive mechanism with viral particles for the ACE2 binding site. We also measured the anti-exopeptidase activity of TNP-1E against ACE2 protein. Collectively, these insights warrant in-depth preclinical development for our nanoprototypes, for example as potential inhalable drug carriers, with the perspective of a clinical translation.
- Hsiai, Tzung,Sanna, Vanna,Satta, Sandro,Sechi, Mario
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- Synthesis of Imidazole and Histidine-Derived Cross-Linkers as Analogues of GOLD and Desmosine
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Amino acid derivatives with a central cationic heterocyclic core (e.g., imidazolium) are biologically relevant cross-linkers of proteins and advanced glycation end (AGE) products. Here, imidazolium-containing cross-linkers were synthesized from imidazole or histidine by N-alkylation employing aspartate- and glutamate-derived mesylates as key step. Biological investigations were carried out to probe the biocompatibility of these compounds.
- Sch?del, Nicole,Icik, Esra,Martini, Maike,Altevogt, Luca,Ramming, Isabell,Greulich, Andreas,Baro, Angelika,Bilitewski, Ursula,Laschat, Sabine
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p. 2260 - 2268
(2021/03/04)
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- N(?)-2-Naphthylmethoxymethyl-Protected Histidines: Scalable, Racemization-Free Building Blocks for Peptide Synthesis
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Histidine (His) racemizes with relative ease during peptide synthesis. One strategy to suppress this racemization is to protect the nitrogen atom of the imidazole moiety in His with a suitable protecting group. Among the numerous protecting groups that have already been tested, the p-methoxybenzyloxymethyl (PMBOM) group on the ?-nitrogen atom effectively suppresses the racemization. However, a large-scale synthesis of N(?)-PMBOM-protected derivatives has hitherto been hampered by the requirement of a freshly prepared unstable reagent. Herein we report the synthesis of N(?)-2-naphthylmethoxymethyl (NAPOM)-protected His derivatives, which can be prepared on a gram scale and do not suffer from the aforementioned instability problems. Furthermore, these NAPOM-protected His derivatives suppress the racemization in Boc- A nd Fmoc-based peptide synthesis.
- Torikai, Kohei,Watanabe, Louis A.,Yanagimoto, Ryota
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p. 448 - 453
(2020/04/08)
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- Intracellular Reactions Promoted by Bis(histidine) Miniproteins Stapled Using Palladium(II) Complexes
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The generation of catalytically active metalloproteins inside living mammalian cells is a major research challenge at the interface between catalysis and cell biology. Herein we demonstrate that basic domains of bZIP transcription factors, mutated to include two histidine residues at i and i+4 positions, react with palladium(II) sources to generate catalytically active, stapled pallado-miniproteins. The resulting constrained peptides are efficiently internalized into living mammalian cells, where they perform palladium-promoted depropargylation reactions without cellular fixation. Control experiments confirm the requirement of the peptide scaffolding and the palladium staple for attaining the intracellular reactivity.
- Gutiérrez-González, Alejandro,Learte-Aymamí, Soraya,Mascare?as, José L.,Vidal, Cristian
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supporting information
p. 9149 - 9154
(2020/04/15)
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- Benzoazepine-Fused Isoindolines via Intramolecular (3 + 2)-Cycloadditions of Azomethine Ylides with Dinitroarenes
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Aminobenzaldehydes bearing a pendant 3,5-dinitrophenyl group react thermally with N-substituted α-amino acids to form unprecedented benzoazepine-fused isoindolines. The reaction proceeds via a dearomatization/rearomatization sequence involving an intramolecular (3 + 2)-cycloaddition between the in situ formed azomethine ylide and the dinitroarene. Various glycine derivatives are tolerated as well as branched substrates based on cyclic, α-mono-, and α,α-disubstituted amino acids, giving single diastereomers in many cases. The method is scalable and gives products with a nitro group ready for further manipulation.
- Wales, Steven M.,Rivinoja, Daniel J.,Gardiner, Michael G.,Bird, Melissa J.,Meyer, Adam G.,Ryan, John H.,Hyland, Christopher J. T.
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supporting information
p. 4703 - 4708
(2019/06/27)
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- Peptide mimetic ligands of polo-like kinase 1 polo box domain and methods of use
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Novel compounds are provided that bind to polo-like kinases through the polo-box domain. In certain embodiments, the novel compounds are PEGylated peptides. The PEGylated peptides in accordance with the invention demonstrate high PBD-binding affinity. In certain embodiments, the PEGylated peptides have also achieved activities in whole cell systems. The invention also provides compounds that bind polo-like kinases through the polo-box domain and possess reduced anionic charge. Further provided are methods of design and/or synthesis of the PEGylated peptides and methods of use thereof. The invention provides methods of use of the compounds and methods of synthesis of the compounds.
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Page/Page column 160
(2019/05/09)
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- Preparation method of N (tau)-methyl-L-histidine derivative and application of derivative in synthesis of anserine
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The invention provides a preparation method of an N (tau)-methyl-L-histidine derivative and a method for preparing anserine through the synthesized N (tau)-methyl-L-histidine derivative. According tothe method, raw materials are cheap and easy to obtain, the selectivity is good, and the yield is high; the operation is simple and practicable, the process is stable, the control is easy, the treatment after reaction is convenient, the product yield is good, the purity is high, and the preparation method can be economically and conveniently used for industrialized production.
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Paragraph 0039; 0040; 0041; 0042
(2018/11/22)
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- Cysteine as a sustainable sulfur reagent for the protecting-group-free synthesis of sulfur-containing amino acids: Biomimetic synthesis of l-ergothioneine in water
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Biomass-derived cysteine was used as a sustainable sulfur source for the synthesis of rare sulfur-containing amino acids, such as l-ergothioneine (4), which might be a new vitamin, and various l- or d-2-thiohistidine compounds. Key in this simple, one-pot two-step procedure in water is a bromine-induced regioselective introduction of cysteine followed by a novel thermal cleavage reaction in the presence of thiols, a safer alternative to hazardous red phosphorus. Besides avoiding hazardous sulfur reagents, the new protecting-group-free approach reduces drastically the total number of steps, compared to described procedures. The main drawback, i.e. handling of liquid bromine as an activating and oxidizing reagent in water, was addressed by evaluating four alternative methods using in situ generation of bromine or HOBr, and first encouraging results are described.
- Erdelmeier, Irene,Daunay, Sylvain,Lebel, Remi,Farescour, Laurence,Yadan, Jean-Claude
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p. 2256 - 2265
(2012/09/08)
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- Investigation of unanticipated alkylation at the N(π) position of a histidyl residue under Mitsunobu conditions and synthesis of orthogonally protected histidine analogues
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We had previously reported that Mitsunobu-based introduction of alkyl substituents onto the imidazole N(π)-position of a key histidine residue in phosphothreonine-containing peptides can impart high binding affinity against the polo-box domain of polo-like kinase 1. Our current paper investigates the mechanism leading to this N(π)-alkylation and provides synthetic methodologies that permit the facile synthesis of histidine N(π)-modified peptides. These agents represent new and potentially important tools for biological studies.
- Qian, Wenjian,Liu, Fa,Burke, Terrence R.
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experimental part
p. 8885 - 8890
(2011/12/21)
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- NOVEL SALTS, POLYMORPHS, AND SYNTHETIC PROCESSES REGARDING IMIDAZOLE DERIVATIVE
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The present invention relates to a process for producing 2-[1-(S)-carboxy-2(S)-[3-(3,5-dichloro-benzyl)-3H-imidazol-4-yl]-ethylamino]-4-methyl-pentanoic acid, as well as novel salts, including hydrates and solvates thereof, and novel crystalline and amorp
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Page/Page column 11
(2012/01/13)
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- Brucella suis histidinol dehydrogenase: Synthesis and inhibition studies of a series of substituted benzylic ketones derived from histidine
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Brucella spp. is the causative agent of brucellosis (Malta fever), which is the most widespread zoonosis worldwide. The pathogen is capable of establishing persistent infections in humans which are extremely difficult to eradicate even with antibiotic therapy. Moreover, Brucella is considered as a potential bioterrorism agent. Histidinol dehydrogenase (HDH, EC 1.1.1.23) has been shown to be essential for the intramacrophagic replication of this pathogen. It therefore constitutes an original and novel target for the development of anti-Brucella agents. In this work, we cloned and overexpressed the HDH-encoding gene from Brucella suis, purified the protein and evidenced its biological activity. We then investigated the inhibitory effects of a series of substituted benzylic ketones derived from histidine. Most of the compounds reported here inhibited B. suis HDH in the lower nanomolar range and constitute attractive candidates for the development of novel anti-Brucella agents.
- Abdo, Marie-Rose,Joseph, Pascale,Boigegrain, Rose-Anne,Liautard, Jean-Pierre,Montero, Jean-Louis,Koehler, Stephan,Winum, Jean-Yves
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p. 4427 - 4433
(2008/03/13)
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- ACRYLAMIDE DERIVATIVES AS VLA-1 INTEGRIN ANTAGONISTS AND USES THEREOF
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Compounds that are VLA-1 integrin antagonists are disclosed. Also disclosed are compositions containing such compounds, and methods of using such compounds in treating diseases mediated, at least in part, by the VLA-1 integrin.
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Page/Page column 228
(2010/02/10)
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- Rapid and facile Lewis acid catalysed Boc protection of amines
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Efficient Boc protection of amines using (Boc)2O in the presence of a catalytic amount of ZrCl4 (10 mol %) in acetonitrile at room temperature is reported with short reaction times and high yields. Efficient Boc protection of amines was carried out using (Boc)2O in the presence of a catalytic amount of ZrCl4 (10 mol %) in acetonitrile at room temperature. The reaction times are very short and the yields are generally high.
- Sharma,Janardhan Reddy,Sree Lakshmi,Radha Krishna, Palakodety
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p. 6963 - 6965
(2007/10/03)
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- Substrate-based design of the first class of angiotensin-converting enzyme-related carboxypeptidase (ACE2) inhibitors
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Angiotensin-converting enzyme-related carboxypeptidase (ACE2) is a recently identified zinc metalloprotease with carboxypeptidase activity that was identified using our genomics platform. We implemented a rational design approach to identify potent and se
- Dales, Natalie A.,Gould, Alexandra E.,Brown, James A.,Calderwood, Emily F.,Guan, Bing,Minor, Charles A.,Gavin, James M.,Hales, Paul,Kaushik, Virendar K.,Stewart, Michael,Tummino, Peter J.,Vickers, Chad S.,Ocain, Timothy D.,Patane, Michael A.
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p. 11852 - 11853
(2007/10/03)
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- Synthesis of potent inhibitors of histidinol dehydrogenase
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Novel inhibitors of histidinol dehydrogenase are described. The most potent inhibitors, compounds 18 (K(i)* = 4.4 nM) and 19 (K(i)* = 2.9 nM) exploit a hitherto unreported lipophilic binding pocket adjoining the active site. Preliminary SAR data for this pocket are detailed. The electrophilic ketone 6 designed to bind to an active site nucleophile was a considerably weaker inhibitor (IC50 ~ 20 μM).
- Dancer, Jane E.,Ford, Mark J.,Hamilton, Kenneth,Kilkelly, Michael,Lindell, Stephen D.,O'Mahony, Mary J.,Saville-Stones, Elizabeth A.
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p. 2131 - 2136
(2007/10/03)
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- Synthesis of L-(+)-ergothioneine
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The first synthesis of L-(+)-ergothioneine (1), a rare natural amino acid, is described. The key step is the direct transformation of the imidazole derivative 11 into imidazole-2-thione 12. This reaction consists of the cleavage and the re-formation of imidazole ring (ANRORC) with phenyl chlorothionoformate via a Bamberger-type intermediate. The conditions used are mild enough to preserve the asymmetric center at the 1a-carbon. The release of enantiomerically pure L-ergothioneine (1) from the ammonium derivative 15 was performed under acidic conditions to avoid the very easy racemization of the betaine function. An efficient and high-yield sypthesis of 2-mercapto-L-histidine (2) which uses the new imidazole-2-thione formation reaction is also described.
- Xu,Yadan
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p. 6296 - 6301
(2007/10/03)
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- N-HETEROCYCLIC ALCOHOL DERIVATIVES
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Compounds of the formula STR1 wherein R 1 is an N-heterocyclic group as defined herein, are disclosed. These compounds are inhibitors of renin and therefore useful as cardiovascular agents.
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- Regiospecific Synthesis of 3-Substituted L-Histidines
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3-Substituted L-histidine derivatives were prepared by a regiospecific alkylation of N,1-bis-Boc-L-histidine methyl ester with in situ-generated alkyl triflates, benzyl triflates, and benzyl mesylates.Subsequent acid hydrolysis of N-Boc and methyl ester p
- Hodges, John C.
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- Further Studies on the Protection of Histidine Side Chains in Peptide Synthesis: The Use of the ?-Benzyloxymethyl Group
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Further studies on the use in peptide synthesis of N(?)-phenacyl protection for histidine side chains have shown that whilst this prevents the side chain-induced racemization which can occur if there is a lone pair of electrons available at the ?-nitrogen, there are concomitant drawbacks.As an alternative approach to the racemisation problem, the effect of halogenation of the heterocyclic ring carbons (to diminish the availability of the ?-nitrogen lone pair) has been investigated.This gives derivatives which are convenient in both classical and solid-phase applications, the halogen modifying groups being removed at the last stage by catalytic hydrogenolysis over a rhodium catalyst.Racemization is suppressed as expected, but it is not eleminated completely: direct blockade of the ?-nitrogen appears to be indispensable for its complete prohibition.Protection of the ?-nitrogen with a benzyloxymethyl group has now been found to be much more satisfactory than the use of the phenacyl group for this purpose.A ?-benzyloxymethyl substituent not only prohibits side chain-induced racemisation but also gives derivatives with convenient physical properties which can be incorporated into well estblished classical and solid-phase strategies without the need for any novel or additional operations or changes in protocol.The protecting group is stable to basic conditions, to trifluoroacetic acid, and to aqueous solutions of carboxylic acids, but is cleaved cleanly and rapidly by hydrogen bromide in trifluoroacetic acid or by catalytic hydrogenolysis.N(α)-t-Butoxycarbonyl-N(?)-benzyloxymethyl-L-histidine has been prepared in good yield by a simple procedure from an easily accessible intermediate and isolated as a crystalline solid; its use has been demonstrated by a number of exercises including a solid-phase synthesis of 5-isoleucine-angiotensin II and a classical synthesis of trihistidine.
- Brown, Tom,Jones, John H.,Richards, John D.
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p. 1553 - 1562
(2007/10/02)
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- Protection of Histidine Side-chains with ?-Benzyloxymethyl- or ?-Bromobenzyloxymethyl-groups
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N(α)-t-Butoxycarbonyl-N(?)-benzyloxymethyl-L-histidine (1) and N(α)-t-butoxycarbonyl-N(?)-4-bromobenzyloxymethyl-L-histidine (2) have been prepared and shown to be suitable derivatives for peptide synthesis with histidine; the synthetic intermediates had
- Brown, Tom,Jones, John H.
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p. 648 - 649
(2007/10/02)
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