- Solid-phase synthesis and CD spectroscopic investigations of novel β-peptides from L-aspartic acid and β-amino-L-alanine
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(Chemical Equation Presented) A solid-phase synthesis method for the preparation of novel β3 and β2-peptides derived from L-aspartic acid and β-amino-L-alanine, respectively, is described. The methodology allows independent buildup of the β-peptide backbone and the introduction of sequential side chain substitutions. Representative peptides from the two classes, an amino-substituted β3-hexapeptide and an acyl-substituted β2-hexapeptide, have been prepared, and their solution conformation is studied by circular dichroism (CD) spectroscopy.
- Ahmed, Sahar,Beleid, Reem,Sprules, Tara,Kaur, Kamaljit
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Read Online
- A New Type of Safety-catch Linker cleaved by Intramolecular Activation of an Amide Anchorage and allowing Aqueous Processing in Solid-phase Peptide Synthesis
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The N3-phenyloxycarbonyl-L-2,3-diaminopropionic acid residue behaves as a versatile linker displaying high stability under neutral and acidic conditions but undergoes activation under mild alkaline conditions for the release of peptide acids or amides by nucleophilic cleavage.
- Sola, Regine,Saguer, Philippe,David, Marie-Laure,Pascal, Robert
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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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- 2,3-Diaminopropanols obtained from D-serine as intermediates in the synthesis of protected 2,3-L-diaminopropanoic acid (L-DAP) methyl esters
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A synthetic strategy for the preparation of two orthogonally protected methyl esters of the non-proteinogenic amino acid 2,3-l-diaminopropanoic acid (l-Dap) was developed. In these structures, the base-labile protecting group 9-fluorenylmethyloxycarbonyl (Fmoc) was paired to the p-toluensulfonyl (tosyl, Ts) or acid-labile tert-butyloxycarbonyl (Boc) moieties. The synthetic approach to protected l-Dap methyl esters uses appropriately masked 2,3-diaminopropanols, which are obtained via reductive amination of an aldehyde prepared from the commercial amino acid Nα-Fmoc-O-tert-butyl-d-serine, used as the starting material. Reductive amination is carried out with primary amines and sulfonamides, and the process is assisted by the Lewis acid Ti(OiPr)4. The required carboxyl group is installed by oxidizing the alcoholic function of 2,3-diaminopropanols bearing the tosyl or benzyl protecting group on the 3-NH2 site. The procedure can easily be applied using the crude product obtained after each step, minimizing the need for chromatographic purifications. Chirality of the carbon atom of the starting d-serine template is preserved throughout all synthetic steps.
- Aiello, Donatella,Athanassopoulos, Constantinos M.,Mazzotti, Fabio,Siciliano, Carlo,Temperini, Andrea,de Luca, Pierantonio
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- Syntheses of Enantiopure 1,2-Ethylenediamines with Tethered Secondary Amines of the Formula H 2NCH 2CH[(CH 2) nNHMe]NH 2(n = 1-4) from α-Amino Acids: New Agents for Asymmetric Catalysis
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Tris(hydrochloride) adducts of the title compounds-are prepared from the inexpensive α-amino acids H 2 N(C=O)CH 2 CH(NH 2)CO 2 H, HO(C=O)(CH 2) n ′ CH(NH 2)CO 2 H (n ′ = 1, 2), and H2 N(CH 2) 4 CH(NH 2)CO 2 H, respectively (steps/overall yield = 5/32, 7/30, 7/33, 5/38). The NH 2 group that is remote from the secondary amine is installed via BH 3 reduction of an amide [-(C=O)NR 2[ derived?-from an α-amino carboxylic acid. The MeNHCH 2 units are introduced by BH 3 reductions of alkyl carbamate [RO(C=O)NHCH 2-; R = Et, t-Bu] or amide [MeHN(C=O)-] moieties.
- Kabes, Connor Q.,Gunn, Jack H.,Selbst, Maximilian A.,Lucas, Reagan F.,Gladysz, John A.
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p. 3277 - 3285
(2020/11/02)
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- THERAPEUTIC COMPOUNDS AND METHODS
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Disclosed herein are compounds of formula I: (I) or pharmaceutically acceptable salts thereof, wherein R1, R2, and R3 may any of the values defined herein, as well as compositions comprising such compounds. Also disclosed are methods for treating diseases including neurodegenerative disorders such as Parkinson's Disease and Alzheimer's Disease.
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Page/Page column 33
(2020/01/31)
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- High-efficiency preparation method of D-dencichine
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The invention relates to a high-efficiency synthesis method of a hemostasis compound D-dencichine, comprising the following steps: firstly enabling D-serine to react with di-tert-butyl dicarbonate ester to generate Boc-D-serine, then generating Gabriel reaction with hydroxy of methylsulfonyl chloride activated Boc-D--serine to obtain N-alpha-Boc-D-alpha, beta-diaminopro, finally condensing with oxalate mono-methyl ester sylvite then performing hydrolytic acidification to obtain a dencichine crude product, and purifying to obtain a dencichine competitive product, with the product content reaching more than 99.8%. Compared with existing D-dencichine synthesis methods, the reaction condition is more mild, the operation is simple and convenient, the material cost is relatively low, and the hemostasis compound D-dencichine is environment-friendly, is suitable for industrial production, and solves the problem of resource for later development of clinical trial of D-dencichine.
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- Total synthesis of (-)-aplaminal by Buchwald-Hartwig cross-coupling of an aminal
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The concise total synthesis of an unusual alkaloid, aplaminal, has been accomplished. The synthetic feature is the Buchwald-Hartwig cross-coupling between a novel triazabicyclo[3.2.1]octane core and an aromatic bromide. The practicality of our approach provides aplaminal analogs and preliminary structure-cytotoxicity relationships of an aromatic moiety were achieved.
- Ohyoshi, Takayuki,Akemoto, Kei,Taniguchi, Ayaka,Ishihara, Takuma,Kigoshi, Hideo
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p. 18442 - 18444
(2019/12/06)
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- Optimized syntheses of Fmoc azido amino acids for the preparation of azidopeptides
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The rise of CuI-catalyzed click chemistry has initiated an increased demand for azido and alkyne derivatives of amino acid as precursors for the synthesis of clicked peptides. However, the use of azido and alkyne amino acids in peptide chemistry is complicated by their high cost. For this reason, we investigated the possibility of the in-house preparation of a set of five Fmoc azido amino acids: β-azido l-alanine and d-alanine, γ-azido l-homoalanine, δ-azido l-ornithine and ω-azido l-lysine. We investigated several reaction pathways described in the literature, suggested several improvements and proposed several alternative routes for the synthesis of these compounds in high purity. Here, we demonstrate that multigram quantities of these Fmoc azido amino acids can be prepared within a week or two and at user-friendly costs. We also incorporated these azido amino acids into several model tripeptides, and we observed the formation of a new elimination product of the azido moiety upon conditions of prolonged couplings with 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate/DIPEA. We hope that our detailed synthetic protocols will inspire some peptide chemists to prepare these Fmoc azido acids in their laboratories and will assist them in avoiding the too extensive costs of azidopeptide syntheses. Experimental procedures and/or analytical data for compounds 3–5, 20, 25, 26, 30 and 43–47 are provided in the supporting information.
- Pícha, Jan,Budě?ínsky, Milo?,Machá?ková, Kate?ina,Collinsová, Michaela,Jirá?ek, Ji?í
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p. 202 - 214
(2017/04/06)
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- Fluorescently Labeled Amino Acids as Building Blocks for Bioactive Molecules
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A series of twelve fluorescently labeled amino acids were designed by assembling different coumarin, fluorescein, or nitrobenzo-furazan fluorophores with N-protected lysine or 2-aminopropionic acid. The synthesized amino acids were evaluated with regard to their spectroscopic properties. The easy introduction of the amino acids into peptides and peptidomimetics was exemplarily shown for one coumarin-labeled- amino acid.
- H?u?ler, Daniela,Gütschow, Michael
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p. 245 - 255
(2016/01/15)
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- A short, rigid linker between pyrene and guanidiniocarbonyl-pyrrole induced a new set of spectroscopic responses to the ds-DNA secondary structure
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A novel pyrene-guanidiniocarbonyl-pyrrole dye, characterised by a short, rigid linker between the two chromophores, interacts strongly with ds-DNA but only negligibly with ds-RNA. Under neutral conditions the dye shows strong selectivity toward AT-DNA (with respect to GC-DNA). Binding is accompanied by a specific ICD band at 350 nm and fluorescence quenching for all DNAs/RNAs studied. At pH 5 the affinity of the dye is reversed, now favouring GC-DNA over AT-DNA. A strong emission increase for AT-DNA is observed but with quenching for GC-DNA.
- Radi Stojkovi, Marijana,Piotrowski, Patryciusz,Schmuck, Carsten,Piantanida, Ivo
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supporting information
p. 1629 - 1633
(2015/02/19)
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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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- Clickable Cγ-azido(methylene/butylene) peptide nucleic acids and their clicked fluorescent derivatives: Synthesis, DNA hybridization properties, and cell penetration studies
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Synthesis, characterization, and DNA complementation studies of clickable Cγ-substituted methylene (azm)/butylene (azb) azido PNAs show that these analogues enhance the stability of the derived PNA:DNA duplexes. The fluorescent PNA oligomers synthesized by their click reaction with propyne carboxyfluorescein are seen to accumulate around the nuclear membrane in 3T3 cells.
- Jain, Deepak R.,Ganesh, Krishna N.
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p. 6708 - 6714
(2014/08/05)
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- Peptide-catalyzed conversion of racemic oxazol-5(4 H)-ones into enantiomerically enriched α-amino acid derivatives
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We report the development and optimization of a tetrapeptide that catalyzes the methanolytic dynamic kinetic resolution of oxazol-5(4H)-ones (azlactones) with high levels of enantioinduction. Oxazolones possessing benzylic-type substituents were found to perform better than others, providing methyl ester products in 88:12 to 98:2 er. The mechanism of this peptide-catalyzed process was investigated through truncation studies and competition experiments. High-field NOESY analysis was performed to elucidate the solution-phase structure of the peptide, and we present a plausible model for catalysis.
- Metrano, Anthony J.,Miller, Scott J.
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p. 1542 - 1554
(2014/03/21)
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- New 2,3-diaminopropionic acid inhibitors of AGE and ALE formation
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Novel 2,3-diaminopropionic acid-based molecules were synthesised and tested successfully as glyoxal/methylglyoxal scavengers and as AGE inhibitors. Addition of an 8-hydroxyquinoline moiety led to an increase of the overall activity. The compounds tested in this study were also proved to be efficient in trapping ALE precursor malondialdehyde. The Royal Society of Chemistry 2013.
- Audic, Nicolas,Potier, Guy,Sasaki, N. André
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p. 773 - 780
(2013/03/13)
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- Aminomethylene peptide nucleic acid (am -PNA): Synthesis, regio-/stereospecific DNA binding, and differential cell uptake of (α/γ, R / S) am- PNA analogues
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Inherently chiral, cationic am-PNAs having pendant aminomethylene groups at α(R/S) or γ(S) sites on PNA backbone have been synthesized. The modified PNAs are shown to stabilize duplexes with complementary cDNA in a regio- and stereo-preferred manner with γ(S)-am PNA superior to α(R/S)-am PNAs and α(R)-am PNA better than the α(S) isomer. The enhanced stabilization of am-PNA:DNA duplexes is accompanied by a greater discrimination of mismatched bases. This seems to be a combined result of both electrostatic interactions and conformational preorganization of backbone favoring the cDNA binding. The am-PNAs are demonstrated to effectively traverse the cell membrane, localize in the nucleus of HeLa cells, and exhibit low toxicity to cells.
- Mitra, Roopa,Ganesh, Krishna N.
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experimental part
p. 5696 - 5704
(2012/08/07)
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- PNAs grafted with (α/γ, R/S)-aminomethylene pendants: Regio and stereo specific effects on DNA binding and improved cell uptake
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PNAs grafted with cationic aminomethylene (am) pendants on the backbone at the glycyl (α) or ethylenediamine (γ) segments show regio (α/γ) and stereochemistry (R/S) dependent binding with complementary DNA. These are efficiently taken up by cells, with γ(S-am) aeg-PNA being the best in all properties.
- Mitra, Roopa,Ganesh
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supporting information; experimental part
p. 1198 - 1200
(2011/03/20)
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- Design, synthesis, and study of a mycobactin-artemisinin conjugate that has selective and potent activity against tuberculosis and malaria
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Although the antimalarial agent artemisinin itself is not active against tuberculosis, conjugation to a mycobacterial-specific siderophore (microbial iron chelator) analogue induces significant and selective antituberculosis activity, including activity against multi- and extensively drug-resistant strains of Mycobacterium tuberculosis. The conjugate also retains potent antimalarial activity. Physicochemical and whole-cell studies indicated that ferric-to-ferrous reduction of the iron complex of the conjugate initiates the expected bactericidal Fenton-type radical chemistry on the artemisinin component. Thus, this "Trojan horse" approach demonstrates that new pathogen-selective therapeutic agents in which the iron component of the delivery vehicle also participates in triggering the antibiotic activity can be generated. The result is that one appropriate conjugate has potent and selective activity against two of the most deadly diseases in the world.
- Miller, Marvin J.,Walz, Andrew J.,Zhu, Helen,Wu, Chunrui,Moraski, Garrett,Moellmann, Ute,Tristani, Esther M.,Crumbliss, Alvin L.,Ferdig, Michael T.,Checkley, Lisa,Edwards, Rachel L.,Boshoff, Helena I.
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supporting information; experimental part
p. 2076 - 2079
(2011/04/16)
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- Inhibition of glyoxalase I: The first low-nanomolar tight-binding inhibitors
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A series of rational modifications to the structure of known S-(N-aryl-N-hydroxycarbamoyl)glutathione-based glyoxalase I inhibitors culminated in the discovery of the first single-digit nanomolar inhibitor. This study makes available key information about possible means to address the issues of metabolic instability, low potency, and synthetic complexicity that have plagued the area of glyoxalase I inhibition. Knowledge garnered from this study has implications in the design of inhibitors with higher conformational definition and lower peptidic character.
- More, Swati S.,Vince, Robert
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body text
p. 4650 - 4656
(2010/03/01)
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- Chemoenzymatic and chemical routes to the nonproteinaceous amino acid albizziine and its amide derivative
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A two-step route for the synthesis of albizziine from Na-Boc-asparagine which proceeds in 65% overall yield is disclosed. A high-yielding, six-step route for the synthesis of its protected amido derivative gives rapid access to a key component of the complex aminopolyol natural product, zwittermicin A. Georg Thieme Verlag Stuttgart.
- Dobrovinskaya, Nina A.,Archer,Hulme, Alison N.
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p. 513 - 516
(2008/12/21)
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- Design, synthesis and biological evaluation of glutathione peptidomimetics as components of anti-Parkinson prodrugs
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Plethoras of CNS-active drugs fail to effect their pharmacologic response due to their in vivo inability to cross the blood-brain barrier (BBB). The classical prodrug approach to overcome this frailty involves lipophilic derivatives of the polar drug, but we herein report a novel approach by which endogenous transporters at BBB are exploited for brain drug delivery. The crucial role played by glutathione in pathogenesis of Parkinson's and the presence of its influx transporters at the basolateral membrane of BBB served as the basis for our anti-Parkinson prodrug design strategy. A metabolically stable analogue of glutathione is used as a carrier for delivery of dopamine and adamantamine. An account of successful syntheses of these prodrugs along with their transport characteristics and stability determination is discussed.
- More, Swati S.,Vince, Robert
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supporting information; experimental part
p. 4581 - 4588
(2009/06/06)
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- Mapping the landscape of potentially primordial informational oligomers: Oligodipeptides and oligodipeptoids tagged with triazines as recognition elements
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(Chemical Equation Presented) Pairing up: Oligodipeptide, oligodeoxy-dipeptide, or oligodipeptoid backbones tagged with the 2,4-diaminotriazine nucleus pair strongly with complementary DNA and RNA. This is in sharp contrast with the behavior of the 2,4-dioxotriazine nucleus, which does not act as a nucleo-base in these systems.
- Mittapalli, Gopi Kumar,Reddy, Kondreddi Ravinder,Xiong, Hui,Munoz, Omar,Han, Bo,De Riccardis, Francesco,Krishnamurthy, Ramanarayanan,Eschenmoser, Albert
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p. 2470 - 2477
(2008/03/11)
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- A metabolically stable tight-binding transition-state inhibitor of glyoxalase-I
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The design, synthesis, and enzyme kinetics evaluation of a transition-state inhibitor of glyoxalase-I is described. The union of the hydroxamic acid zinc-chelator with a urea isostere for the glu-cys amide bond led to a glutathione analog which retained inhibitory potency toward glyoxalase-I while possessing resistance toward γ-glutamyltranspeptidase mediated breakdown. This compound is viewed as a potential lead for the development of second-generation glyoxalase-I inhibitors wherein, the problems pertaining to metabolism and selectivity are overcome.
- More, Swati S.,Vince, Robert
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p. 6039 - 6042
(2007/10/03)
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- Proteasome inhibitors and methods of using the same
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The present invention provides boronic acid compounds, boronic esters, and compositions thereof that can modulate apoptosis such as by inhibition of proteasome activity. The compounds and compositions can be used in methods of inducing apoptosis and treating diseases such as cancer and other disorders associated directly or indirectly with proteasome activity.
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Page/Page column 44
(2008/06/13)
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- PROTEASOME INHIBITORS AND METHODS OF USING THE SAME
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The present invention provides boronic acid compounds, boronic esters, and compositions thereof that can modulate apoptosis such as by inhibition of proteasome activity. The compounds and compositions can be used in methods of inducing apoptosis and treating diseases such as cancer and other disorders associated directly of indirectly with proteasome activity.
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Page/Page column 223-224
(2008/06/13)
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- Studies on the mechanism of 1,2-dihydropyrazin-2-one ring formation from dipeptidyl chloromethyl ketone and its chemical properties: Immediate deamination during catalytic hydrogenation
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1,2-Dihydropyrazin-2-one derivatives, which have two aminoalkyl groups at the positions 3 and 6, were found to be efficient tools for the construction of potent, selective and long-acting opioid mimetics. During the course of preparation, we found that the catalytic hydrogenation of 3,6- bis(benzyloxycarbonylaminomethyl)-5-methyl-1,2-dihydropyrazin-2-one to remove the benzyloxycarbonyl groups resulted in a side reaction. By MS and NMR studies and by preparation of additional 1,2-dihydropyrazin-2-one derivatives, the structure of the by-product was identified as 3-aminomethyl-5,6-dimethyl-1,2- dihydropyrazin-2-one. Preparation of additional compounds substituted with deuterium provided us with sufficient information to confirm the structure of the product and to support a cyclization mechanism in its formation.
- Miyazaki, Anna,Fujisawa, Yutaka,Shiotani, Kimitaka,Fujita, Yoshio,Li, Tingyou,Tsuda, Yuko,Yokoi, Toshio,Bryant, Sharon D.,Lazarus, Lawrence H.,Okada, Yoshio
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p. 1152 - 1158
(2007/10/03)
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- An Efficient Synthesis of a Probe for Protein Function: 2,3-Diaminopropionic Acid with Orthogonal Protecting Groups
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(Matrix presented) An efficient and cost-effective synthesis of N(α)-Boc2-N(β)-Cbz-2,3-diaminopropionic acid is reported. The synthesis starts from commercially available N(α)-Boc-Asp(OBn)-OH and employs a Curtius rearrangement to establish the β-nitrogen. Proper protection of the α-nitrogen is essential for the success of the Curtius rearrangement.
- Englund, Ethan A.,Gopi, Hosahudya N.,Appella, Daniel H.
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p. 213 - 215
(2007/10/03)
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- Novel inhibitors of procollagen C-terminal proteinase. Part 1: Diamino acid hydroxamates
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The parallel synthesis of novel inhibitors of procollagen C-terminal proteinase is described. The synthetic strategy allowed for the facile synthesis of a large number of side-chain diversified diamino acid hydroxamates, of which the D-diaminopropionic acid derivatives were shown to be single digit nanomolar PCP inhibitors.
- Delaet,Robinson,Wilson,Sullivan,Bradley,Dankwardt,Martin,Van Wart,Walker
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p. 2101 - 2104
(2007/10/03)
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- Synthesis of aza and oxaglutamyl-p-nitroanilide derivatives and their kinetic studies with γ-glutamyltranspeptidase
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A new series of L-glutamic acid p-nitroanilide analogues has been synthesized and tested as substrates and inhibitors of rat kidney γ-glutamyltranspeptidase (GGT). Kinetic parameters (Km and kcat) were determined for each analogue and provide insight into the scope and limits of GGT catalytic efficiency.
- Lherbet, Christian,Morin, Mylene,Castonguay, Roselyne,Keillor, Jeffrey W.
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p. 997 - 1000
(2007/10/03)
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- The design, synthesis, and biological evaluation of analogues of the serine-threonine protein phosphatase 1 and 2A selective inhibitor microcystin LA: Rational modifications imparting PP1 selectivity
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Based on the results from previously reported molecular modeling analyses of the interactions between the inhibitor microcystin and the serine-threonine protein phosphatases 1 and 2A, we have designed analogues of microcystin LA with structural modifications intended to impart PP1 selectivity. The synthesis of several first generation analogues followed by inhibition assays revealed that all three are PP1-selective, as predicted. Although the observed selectivities are modest, one of the designed analogues is more selective for PP1 than any known small molecule inhibitor. Copyright (C) 1999 Elsevier Science Ltd.
- Aggen, James B.,Humphrey, John M.,Gauss, Carla-Maria,Huang, Hsien-Bin,Nairn, Angus C.,Chamberlin, A. Richard
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p. 543 - 564
(2007/10/03)
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- Synthesis and study of peptides with semirigid i and i+7 side-chain bridges designed for α-helix stabilization
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A search for conformational constraints on the peptide α-helical conformation indicated that para-substituted amino acid derivatives of a benzene ring might be suitable for linking pairs of side chains that are separated by two turns of the helix. A 14-residue synthetic, amphiphilic α-helical peptide model system has been used to study the helix stabilizing effects of a series of four such bridges having constitutionally isomeric structures. These bridges were used to link positions 3 and 10 of the model peptides. The peptides were synthesized in good yield by standard solid-phase methods, including cyclization on the solid support. They were then studied for their solution conformations and melting behavior by circular dichroism (CD) spectropolarimetry, and for their elution behavior on reversed-phase HPLC columns. In aqueous solution and in 50% (v/v) trifluoroethanol, the most effective bridge for helix stabilization consisted of a 4-(aminomethyl)phenylacetic acid residue (AMPA) linked by amide bonds to the side chain functional groups of a (S)-2,3-diaminopropionic acid residue (Dap) in position 3 of the model peptide and an aspartic acid residue in position 10. This Dap3(AMPA), Asp10 bridge was about as effective as two Lys(i), Asp(i+4) lactam bridges incorporated linking residues 3 and 7, and 10 and 14, in the same model peptide sequence. This suggests that it is worth about 1kcal/mol of helix stabilization energy. Copyright (C) 1999 Elsevier Science Ltd.
- Yu, Chongxi,Taylor, John W.
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p. 161 - 175
(2007/10/03)
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- Studies related to the absolute configuration of cyclocinamide A: Total synthesis of 4(R),11(R)-cyclocinamide A
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Coupling of the fluorenylmethyl ester 3 (R = Fm) of (S)-5- bromotryptophan with N(α)-BOC-(S)-asn-O-benzoyl-(R)-ise 9 gave rise to tripeptide 10. Cleavage of the BOC group in 10 followed by coupling with N(α)-BOC-N(β)-Fmoc-(R)-2,3-diaminopropanoic acid afforded tetrapeptide 11 which was transformed into cyclic peptide 12. Cleavage of the BOC in 12 followed by coupling with the glycine derived side chain 14 gave rise, after removal of the benzoyl group to 4(R),11(R)-cyclocinamide A(2) which was not identical to natural cyclocinamide A(1), suggesting that 1 possesses the 4(S),7(S),11(S),14(S) configuration.
- Grieco, Paul A.,Reilly, Michael
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p. 8925 - 8928
(2007/10/03)
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- Rearrangement of Nα-Protected L-Asparagines with Iodosobenzene Diacetate. A Practical Route to β-Amino-L-alanine Derivatives
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A general synthetic method for the Hofmann rearrangement of protected asparagines has been developed. Reaction of asparagine derivatives with iodosobenzene diacetate (PIDA) in mixed solvents produces β-amino-L-alanines in good yield. Advantages over the commonly used reagent bis(trifluoroacetoxy)iodobenzene have been discussed.
- Zhang, Lin-Hua,Kauffman, Goss S.,Pesti, Jaan A.,Yin, Jianguo
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p. 6918 - 6920
(2007/10/03)
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- Synthesis of [L-3-deoxymimosine4]-angiotensin I as an approach to the preparation of selective protein-tyrosine kinase (PTK) inhibitors
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tert-Boc-L-3-Deoxymimosine (13) and tert-Boc-D-Deoxymimosine (16) were prepared in two steps from tert-Boc-L-asparagine and tert-Boc-D-asparagine, respectively. Both 13 and 16 were determined to be optically pure by derivatization with Marphey's reagent. Activation and coupling of 16 to L-isoleucine methyl ester resulted in a diastereomeric mixture of products containing 96% of the DL diastereomer and 4% of the LL diastereomer. [L-3-Deoxymimosine4]-angiotensin I was synthesized from 13 as an approach to the design and synthesis of selective protein-tyrosine kinase (PTK) inhibitors.
- Lee, Eung-Seok,Jurayj, Jurjus,Cushman, Mark
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p. 9873 - 9882
(2007/10/02)
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- Synthesis of chiral isoxazolidin-5-ones and their applications to the synthesis of β-amino-alanines and β-(N-hydroxyamino)-alanines
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Herein we report a high-yielding synthesis of isoxazolidin-5-ones and their use to synthesise both β-amino-alanines and β-(N-hydroxyamino)-alanines.
- Baldwin, Jack E.,Adlington, Robert M.,Mellor, Lisa C.
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p. 5049 - 5066
(2007/10/02)
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- Synthesis of Peptides Containing Unnatural, Metal-Ligating Residues: Aminodiacetic Acid as a Peptide Side Chain
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Peptides possessing a pair of residues separated by one turn in the α-helical conformation and potentially capable of ligating a single metal ion in aqueous solution were designed.It was predicted that the resulting cross-link would shift toward α-helix the random coil/α-helix equilibrium.The syntheses of 10 peptides Ac-AdalAlamAdal(Ala4GluLys)n-NH2 where Adal is an L-α-amino acid residue with an aminodiacetic acid bearing side chain, -(CH2)lN(CH2CO2H)2 (with values of l, m and n as follows: 1, 2, 3 (1); 1, 3, 1 (2a); 1, 3, 2 (2b); 1, 3, 3 (2c); 2, 2, 3 (3); 2, 3, 3 (4); 3, 2 ,3 (5); 3, 3, 3 (6); 4, 2, 3 (7); 4, 3, 3 (8) are described using Boc chemistry on p-methylbenzhydrylamine resin.The aminodiacetic acid bearing residues were incorporated with side chains protected as the dibenzyl esters.To avoid side reactions, residues Adal for l=1 and 2 were incorporated by a block approach.Peptide structures were confirmed by observation of the predicted parent ions in the FAB MS.The circular dichroism spectra of several of these peptides that possess a pair of metal-ligating residues separated by two or three intervening residues have previously been shown to undergo changes on addition of metal ions consistent with appreciable enhancement of helix content.
- Ruan, Fuqiang,Chen, Yanqiu,Itoh, Katsumi,Sasaki, Tomikazu,Hopkins, Paul B.
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p. 4347 - 4354
(2007/10/02)
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- QUANTITATIVE SYNTHESIS OF L OR D N2-TERTBUTOXYCARBONYL-2,3-DIAMINOPROPANOIC ACID FROM PROTECTED L OR D SERINE-β-LACTONE
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The reaction of ammonia on protected L or D serine-β-lactone was reinvestigated.An easy synthesis of N2-tertbutoxycarbonyl-L-2,3-diaminopropanoic acid (and D enantiomer), an important precursor of several antibiotics is proposed.
- Kucharczyk, N.,Badet, B.,Goffic, F. Le
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p. 1603 - 1610
(2007/10/02)
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