- A versatile and selective chemo-enzymatic synthesis of β-protected aspartic and γ-protected glutamic acid derivatives
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Two versatile, high yielding, and efficient chemo-enzymatic methods for the synthesis of β-protected Asp and γ-protected Glu derivatives using Alcalase are described. The first method is based on the α-selective enzymatic hydrolysis of symmetrical aspartyl and glutamyl diesters. The second method involving mixed diesters comprises a three-step protocol using (i) α-selective enzymatic methyl-esterification, (ii) chemical β-esterification, and finally (iii) α-selective enzymatic methyl ester hydrolysis. The yields of the purified β- and γ-esters range from 77% to 91%.
- Nuijens, Timo,Kruijtzer, John A.W.,Cusan, Claudia,Rijkers, Dirk T.S.,Liskamp, Rob M.J.,Quaedflieg, Peter J.L.M.
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experimental part
p. 2719 - 2721
(2009/09/06)
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- Mapping the landscape of potentially primordial informational oligomers: Oligodipeptides tagged with 2,4-disubstituted 5-aminopyrimidines as recognition elements
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(Chemical Equation Presented) Bit different: 2,4-Dioxo- and 2,4-diamino-5-aminopyrimidine nuclei attached to an oligodipeptide backbone display a disparity in their base-pairing strength which is opposite to that shown by corresponding triazines. This behavior points to a remarkable correlation between pairing strength and ΔpKa values of pairs of complementary bases.
- Mittapalli, Gopi Kumar,Osornio, Yazmin M.,Guerrero, Miguel A.,Reddy, Kondreddi Ravinder,Krishnamurthy, Ramanarayanan,Eschenmoser, Albert
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p. 2478 - 2484
(2008/03/11)
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- Synthesis of functionalized rab GTPases by a combination of solution- Or solid-phase lipopeptide synthesis with expressed protein ligation
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Prenylated proteins with non-native functionalities are generally very difficult to obtain by recombinant or enzymatic means. The semisynthesis of preparative amounts of prenylated Rab guanosine triphosphatases (GTPases) from recombinant proteins and synthetic prenylated peptides depends largely on the availability of functionalised prenylated peptides corresponding to the proteins' native structure or modifications thereof. Here, we describe and compare solution-phase and solid-phase strategies for the generation of peptides corresponding to the prenylated C terminus of Rab7 GTPase. The solid-phase with utilisation of a hydrazide linker emerges as the more favourable approach. It allows a fast and practical synthesis of pure peptides and gives a high degree of flexibility in their modification. To facilitate the analysis of semisynthetic proteins, the synthesised peptides were equipped with a fluorescent group. Using the described approach, we introduced fluorophores at several different positions of the Rab7 C terminus. The position of the incorporated fluorescent groups in the peptides did not influence the protein-ligation reaction, as the generated peptides could be ligated onto thioester-tagged Rab7. However, it was found that the positioning of the fluorescent group had an influence on the functionality of the Rab7 proteins; analysis of the interaction of the semisynthetic Rab7 proteins with REP (Rab escort protein) and GDI (guanosine diphosphate dissociation inhibitor) molecules revealed that modification of the peptide side chains or of the C-terminal isoprenoid did not significantly interfere with complex formation. However, functionalisation of the C terminus was found to have an adverse effect on complex formation and stability, possibly reflecting low structural flexibility of the Rab GDI/REP molecules in the vicinity of the lipid-binding site.
- Brunsveld, Luc,Watzke, Anja,Durek, Thomas,Alexandrov, Kirill,Goody, Roger S.,Waldmann, Herbert
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p. 2756 - 2772
(2007/10/03)
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- Synthesis and electrochemical properties of tetrathiafulvalene derived amino acids and peptides
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A synthetic route to a tetrathiafulvalene (TTF) derived aspartic acid derivative 18, with suitable orthogonal protecting groups has been developed. The aspartic acid derivative 18 can be used in the synthesis of peptides, as exemplified by the synthesis of di-, tri- and tetra-peptides 21-23. Preliminary electrochemical studies of these novel peptides indicate that they may well undergo conformational reorganisation upon oxidation of the TTF moieties.
- Booth, Susan,Wallace, Emma N. K.,Singhal, Kavita,Bartlett, Philip N.,Kilburn, Jeremy D.
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p. 1467 - 1474
(2007/10/03)
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- Combinatorial synthesis and biological evaluation of library of small-molecule Ser/Thr-protein phosphatase inhibitors
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In eukaryotes, phosphorylation of serine, threonine, and tyrosine residues on proteins is a fundamental posttranslational regulatory process for such functions as signal transduction, gene transcription, RNA splicing, cellular adhesion, apoptosis, and cell cycle control. Based on functional groups present in natural product serine/threonine protein phosphatase (PSTPase) inhibitors, we have designed pharmacophore model 1 and demonstrated the feasibility of a combinatorial chemistry approach for the preparation of functional analogues of 1. Preliminary biological testing of 18 structural variants of 1 has identified two compounds with growth inhibitory activity against cultured human breast cancer cells. In vitro inhibition of the PSTPase PP2A was demonstrated with compound Id. Using flow cytometry we observed that compound If caused prominent inhibition in the G1 phase of the cell cycle. Thus, the combinatorial modifications of the minimal pharmacophore 1 can generate biologically interesting antiproliferative agents.
- Wipf, Peter,Cunningham, April,Rice, Robert L.,Lazo, John S.
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p. 165 - 177
(2007/10/03)
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