- Novel design of bicyclic β-turn dipeptides on solid-phase supports and synthesis of [3.3.0]-bicyclo[2,3]-leu-enkephalin analogues
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(Chemical Equation Presented) External bicyclic β-turn dipeptide mimetics provide an excellent design approach that can offer a rich chiral ensemble of structures with different backbone conformations. We report herein a novel design of a convergent combinatorial synthetic methodology, which is illustrated by the solid-phase synthesis of a series of [3.3.0]-bicyclo [2,3]-Leu-enkephalin analogues. The reactions were optimized and the epimeric configurations were determined by 2D NMR spectroscopy. Biological assays show that these analogues have more potent δ binding affinity and bioactivity for δ vs μ opioid receptor, which may be related to the different conformations preferred by these analogues in our modeling studies.
- Gu, Xuyuan,Ying, Jinfa,Agnes, Richard S.,Navratilova, Edita,Davis, Peg,Stahl, Gannon,Porreca, Frank,Yamamura, Henry I.,Hruby, Victor J.
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Read Online
- Development of solid-supported methodology for the preparation of peptidoglycan fragments containing (2S,6R)-diaminopimelic acid
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Herein, we describe the development of an efficient solid-supported methodology for the stereoselective synthesis of two peptides containing (2S,6R)-diaminopimelic acid, (S)-Ala-γ-(R)-Glu-(2S,6R)-A2pm-(R)-Ala 1 and γ-(R)-Glu-(2S,6R)-A2pm 2. The platform consists of a Wang resin anchored by an amino acid chain including allylglycine. By olefin cross metathesis with vinylglycine, unsaturated protected (2S,6R)-A2pm was fixed on solid support. Peptides were achieved by cleavage of cross metathesis products from resin, followed by reduction of double bonds along removing of protecting groups. Furthermore, this efficient solid phase approach will lead to peptide and muropeptide libraries.
- Simon, Justine F.,Lamborelle, Nicolas,Zervosen, Astrid,Lemaire, Christian,Joris, Bernard,Luxen, André
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- Fungal Dioxygenase AsqJ Is Promiscuous and Bimodal: Substrate-Directed Formation of Quinolones versus Quinazolinones
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Previous studies showed that the FeII/α-ketoglutarate dependent dioxygenase AsqJ induces a skeletal rearrangement in viridicatin biosynthesis in Aspergillus nidulans, generating a quinolone scaffold from benzo[1,4]diazepine-2,5-dione substrates. We report that AsqJ catalyzes an additional, entirely different reaction, simply by a change in substituent in the benzodiazepinedione substrate. This new mechanism is established by substrate screening, application of functional probes, and computational analysis. AsqJ excises H2CO from the heterocyclic ring structure of suitable benzo[1,4]diazepine-2,5-dione substrates to generate quinazolinones. This novel AsqJ catalysis pathway is governed by a single substituent within the complex substrate. This unique substrate-directed reactivity of AsqJ enables the targeted biocatalytic generation of either quinolones or quinazolinones, two alkaloid frameworks of exceptional biomedical relevance.
- Einsiedler, Manuel,Jamieson, Cooper S.,Maskeri, Mark A.,Houk, Kendall N.,Gulder, Tobias A. M.
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supporting information
p. 8297 - 8302
(2021/03/01)
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- Macrocyclic BACE1 inhibitors with hydrophobic cross-linked structures: Optimization of ring size and ring structure
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Based on the X-ray crystallography of recombinant BACE1 and a hydroxyethylamine-type peptidic inhibitor, we introduced a cross-linked structure between the P1 and P3 side chains of the inhibitor to enhance its inhibitory activity. The P1 and P3 fragments bearing terminal alkenes were synthesized, and a ring-closing metathesis of these alkenes was used to construct the cross-linked structure. Evaluation of ring size using P1 and P3 fragments with various side chain lengths revealed that 13-membered rings were optimal, although their activity was reduced compared to that of the parent compound. Furthermore, the optimal ring structure was found to be a macrocycle with a dimethyl branched substituent at the P3 β-position, which was approximately 100-fold more active than the non-substituted macrocycle. In addition, the introduction of a 4-carboxymethylphenyl group at the P1′ position further improved the activity.
- Otani, Takuya,Hattori, Yasunao,Akaji, Kenichi,Kobayashi, Kazuya
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- Divergent Access to Histone Deacetylase Inhibitory Cyclopeptides via a Late-Stage Cyclopropane Ring Cleavage Strategy. Short Synthesis of Chlamydocin
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A unified step-economical strategy for accessing histone deacetylase inhibitory peptides is proposed, based on the late-stage installation of multiple zinc-binding functionalities via the cleavage of the strained cyclopropane ring in the common pluripoten
- Elek, Gábor Zoltán,Koppel, Kaur,Zubrytski, Dzmitry M.,Konrad, Nele,J?rving, Ivar,Lopp, Margus,Kananovich, Dzmitry G.
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supporting information
p. 8473 - 8478
(2019/10/16)
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- Insight into Transannular Cyclization Reactions to Synthesize Azabicyclo[X.Y.Z]alkanone Amino Acid Derivatives from 8-, 9-, and 10-Membered Macrocyclic Dipeptide Lactams
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An efficient method for synthesizing different functionalized azabicyclo[X.Y.0]alkanone amino acid derivatives has been developed employing electrophilic transannular cyclizations of 8-, 9-, and 10-membered unsaturated macrocycles to form 5,5-, 6,5-, 7,5-, and 6,6-fused bicylic amino acids, respectively. Macrocycles were obtained by a sequence featuring peptide coupling of vinyl-, allyl-, homoallyl-, and homohomoallylglycine building blocks followed by ring-closing metathesis. X-ray crystallographic analyses of the 8-, 9-, and 10-membered macrocyclic lactam starting materials as well as certain bicyclic amino acid products provided insight into their conformational preferences as well as the mechanism for the diastereoselective formation of specific azabicycloalkanone amino acids by way of transannular iodolactamization reactions. (Chemical Equation Presented).
- Atmuri, N. D. Prasad,Lubell, William D.
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p. 4904 - 4918
(2015/06/02)
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- Methods for the synthesis of dicarba bridges in organic compounds
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The present invention relates to methods for forming dicarba bridges in organic compounds. This involves the use of a pair of complementary metathesisable groups on the organic compound, and subjecting the compound to cross-metathesis under microwave radiation conditions. In an alternative, the compounds contain a turn-inducing group between the pair of cross-metathesisable groups to facilitate the cross-metathesis.
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Page/Page column 151
(2015/11/17)
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- Influence of α-methylation in constructing stapled peptides with olefin metathesis
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Ring-closing metathesis is commonly utilized in peptide macro-cyclization. The influence of α-methylation of the amino acids bearing the olefin moieties has never been systematically studied. In this report, controlled reactions unambiguously indicate that α-methylation at the N-terminus of the metathesis sites is crucial for this reaction to occur. Also, we first elucidated that the E-isomers of stapled peptides are significantly more helical than the Z-isomers.
- Zhang, Qingzhou,Shi, Xiaodong,Jiang, Yanhong,Li, Zigang
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p. 7621 - 7626
(2014/12/11)
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- Synthesis of conformationally constrained γ-d-glutamyl-meso- diaminopimelic acid derivatives as ligands of nucleotide-binding oligomerization domain protein 1 (Nod1)
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Nod1, an important member of the pattern recognition receptor family, remains a virtually unexploited target. Harnessing its innate immune stimulatory properties still remains an unfulfilled goal of medicinal chemistry. Nucleotide-binding oligomerization domain protein 1 (Nod1) agonists have been shown to boost the inflammatory responses against pathogenic microbes and could thus constitute a new class of broad spectrum antimicrobial agents. To gain additional insight into the structure/activity relationships of Nod1 agonistic compounds, a series of novel, conformationally constrained γ-d-glutamyl- meso-diaminopimelic acid (iE-DAP) analogs have been designed and synthesized. Ramos-Blue cells expressing Nod1 were used to screen and validate our compounds for their Nod1-agonist activity. Their immunomodulatory properties were subsequently determined in vitro, by evaluating their capacity to induce pro-inflammatory cytokine and chemokine production from human peripheral blood mononuclear cells (PBMC), by themselves and in synergy with lipopolysaccharide (LPS), a Toll-like receptor 4 (TLR4) ligand. The synthesized iE-DAP analogs were shown to possess immuno-enhancing properties as a result of their potent and specific Nod1-agonistic effect. The activity of the compound exhibiting the greatest capacity to induce pro-inflammatory cytokine release from PBMC surpassed that of lauroyl-γ-d-glutamyl-meso-diaminopimelic acid (C12-iE-DAP).
- Jakopin, ?iga,Gobec, Martina,Kodela, Jaka,Hazdovac, Toni,Mlinari?-Ra??an, Irena,Sollner Dolenc, Marija
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p. 232 - 243
(2013/10/01)
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- PHIP-label: Parahydrogen-induced polarization in propargylglycine- containing synthetic oligopeptides
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The unsaturated side chain of l-propargylglycine (Pra) was used to study parahydrogen-induced polarization (PHIP) in synthetic oligopeptides. For the first time PHIP-induced NMR signal enhancement was demonstrated using model peptides bearing various func
- Koerner, Marco,Sauer, Grit,Heil, Andreas,Nasu, Daichi,Empting, Martin,Tietze, Daniel,Voigt, Stephan,Weidler, Heiko,Gutmann, Torsten,Avrutina, Olga,Kolmar, Harald,Ratajczyk, Tomasz,Buntkowsky, Gerd
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supporting information
p. 7840 - 7841
(2013/09/02)
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- Conotoxin analogues and methods for synthesis of intramolecular dicarba bridge-containing peptides
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According to the present invention, there is provided a range of new conotoxin derivatives and methods for synthesizing these analogues and other intramolecular dicarba bridge-containing peptides, including dicarba-disulfide bridge-containing peptides.
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Page/Page column 74-75
(2010/11/28)
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- Systematic study of the synthesis of macrocyclic dipeptide β-turn mimics possessing 8-, 9-, and 10- membered rings by ring-closing metathesis
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A systematic study was performed to establish general synthesis protocols for forming enantiomerically pure macrocyclic dipeptide lactams. Focusing on macrocycles of 8-, 9-, and 10-membered rings, effective syntheses were achieved by a sequence featuring
- Kaul, Ramesh,Surprenant, Simon,Lubell, William D.
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p. 3838 - 3844
(2007/10/03)
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- Design and synthesis of new bicyclic diketopiperazines as scaffolds for receptor probes of structurally diverse functionality
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Diketopiperazines (DKPs) are a common motif in various biologically active natural products, and hence they may be useful scaffolds for the rational design of receptor probes and therapeutic agents. We constructed a new bicyclic scaffold that combines a D
- Besada, Pedro,Mamedova, Liaman,Thomas, Craig J.,Costanzi, Stefano,Jacobson, Kenneth A.
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p. 2016 - 2025
(2007/10/03)
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- Convenient access to glutamic acid side chain homologues compatible with solid phase peptide synthesis
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(Chemical Equation Presented) Preparation of several side chain length variants of glutamic acid is achieved via olefin cross metathesis of allyl glycine derivatives. The products are suitably protected for direct use in Fmoc solid-phase peptide synthesis, as demonstrated by successful synthesis of test sequences.
- Ryan, Shannon J.,Zhang, Yongda,Kennan, Alan J.
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p. 4765 - 4767
(2007/10/03)
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- Non-destructive Cleavage of N-Acylsultams Under Neutral Conditions: Preparation of Enantiomerically, Pure Fmoc-Protected α-Amino Acids
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Heating diastereoisomerically pure N-acylsultams 3 or 4 with allyl alcohol/Ti(OR)4 efficiently yields sultams 1 or 2 and allyl esters 5.Esters 5 are hydrolyzed under nonbasic conditions in the presence of Wilkinson's catalyst to give enantiomerically and diastereoisomerically pure carboxylic acids 7.A series of carbonyl-(Fmoc)-protected amino acids 14 were thus prepared from N-acylsultams 12.
- Oppolzer, Wolfgang,Lienard, Philippe
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p. 2572 - 2582
(2007/10/02)
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