- MACROCYCLIZATION OF PEPTIDOMIMETICS
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The invention provides an improved method of macrocyclization of peptidomimetics, as measured by isolated yields and product distribution, which comprises substitution of one or more of the backbone amide C=O bonds with a turn-inducing motif. The method is general with enhancements seen across a range of ring sizes (e.g. tri-, tetra-, penta- and hexapeptides). Specifically, the invention provides a peptidomimetic macrocycle comprising a carbonyl bioisosteric turn-inducing element having the structure: (I) wherein X is a heteroatom; and wherein R1 to R6 are each independently selected from alkyl, aryl, heteroaryl and H.
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- Synthesis of selenocysteine-containing dipeptides modeling the active site of thioredoxin reductase
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Four cyclic dipeptides modeling the active site of thioredoxin reductase (TrxR), UU, CU, UC, and CC, where U and C represent selenocystine and cystine, respectively, were synthesized and their glutathione peroxidase (GPx)-like catalytic activity was evaluated by the reaction of hydrogen peroxide (H2O2) with glutathione (GSH) in the presence of glutathione reductase (GR). Among these, only UC exhibited the significant antioxidant capacity, suggesting that an atomic environment around the Se–S bond is relevant to the reactivity toward a thiol substrate.
- Shimodaira, Shingo,Iwaoka, Michio
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supporting information
p. 750 - 752
(2019/04/26)
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- Investigation of Cysteine as an Activator of Side-Chain N→S Acyl Transfer and Tail-to-Side-Chain Cyclization
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N→S Acyl transfer is a popular method for the postsynthesis production of peptide C α -thioesters for use in native chemical ligation and for the synthesis of head-to-tail cyclic peptides. Meanwhile thioester formation at the side chain of aspartic or glutamic acids, leading to tail-to-side-chain-cyclized species, is less common. Herein we explore the potential for cysteine to function as a latent thioester when appended to the side chain of glutamic acid. Initial insights gained through study of C-terminal β-alanine as a model for the increased chain length were ultimately applied to peptide macrocyclization. Our results emphasize the increased barrier to acyl transfer at the glutamic acid side chain and indicate how a slow reaction, facilitated by cysteine itself, may be accelerated by fine-tuning of the stereoelectronic environment..
- Castillo-Pazos, Durbis J.,Macmillan, Derek
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p. 1923 - 1928
(2017/09/13)
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- Divergent Approach for the Synthesis of Gombamide A and Derivatives
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A synthesis of gombamide A (1) using N-terminal peptide extension, oxidative disulfide bond formation, and late-stage 4-hydroxystyrylamide installation has been achieved. This divergent method was also utilized to synthesize several gombamide A derivative
- Vippila, Mohana Rao,Nikhar, Sameer,Gracia, Alan P.,Cuny, Gregory D.
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supporting information
p. 4726 - 4729
(2016/09/28)
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- Carbohydrate-based VEGF inhibitors
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Cyclic peptide-carbohydrates (compounds 1a-c, 2, 33, 34) were designed and synthesized to act as mimetics of loop 2 of the proangiogenic molecule vascular endothelial growth factor D (VEGF-D). The mimetics were designed to inhibit dimerization of the receptors (VEGFR-2 and VEGFR-3) by VEGF-D, and thus have the potential to inhibit angiogenesis. To this end, in the previously described cyclic octapeptide CNEESLIC and the cyclic nonapeptide CGNEESLIC inhibitors derived from VEGF-D loop 2, the NEES tetrapeptide residue was replaced by a carbohydrate scaffold having the amino acid side chain mimics in positions proposed by modeling studies. Attachment of the additional amino acids using the Fmoc technology, then formation of the cyclic disulfides, and finally total deprotection afforded the target molecules of which 2 and 34 showed an ability to inhibit the biological activity of VEGF-D through VEGFR-2 in cell-based assays, albeit at high mimetic concentration. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.
- Haag, Tobias,Hughes, Richard A.,Ritter, Gerd,Schmidt, Richard R.
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p. 6016 - 6033
(2008/09/17)
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- PYRAZOLOPYRIMIDINONES AS PHOSPHODIESTERASE INHIBITORS
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Compounds of formula (I) wherein R1 is H, C1-C3-alkyl, C3-C5-cycloalkyl or C1-C3-perfluoroalkyl, R2 is H, C1-C6-alkyl optionally substituted by OH, C1
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Page/Page column 14-15
(2008/06/13)
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- Tritiated Peptides. Part 11. Synthesis of 6>-, 11>-, and 6,11>-Somatostatin and the Metabolite 1>-Somatostatin
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The syntheses are described of somatostatin labelled with tritium singly in the phenylalanine residues at positions 6 and 11 and doubly at residues 6 and 11 to specific radioactivities of 15.5, 13.8 and 14.1 Cim mol-1, respectively, by reductive deiodination of fully-protected precursors.Cysteine residues were proteced by S-trityl groups and the disulphide bridge was formed by iodine oxidation of the tritiated protected precursors.The purity of the products was assessed by acidic hydrolysis, ion-exchange and high-pressure liquid chromatography, and by enzymic digestion of the products modified by reduction and aminoethylation.The synthesis of the metabolite 1>-somatostatin is described.The syntheses of 6>-, 11>- and 6,11>-somatostatin are described.
- Allen, Mark C.,Brundish, Derek E.,Martin, John R.,Wade, Roy
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p. 2040 - 2048
(2007/10/02)
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