Synthesis of aliphatic O-dimannosyl amino acid building blocks for solid-phase assembly of glycopeptide libraries

1995 ◽  
pp. 2883 ◽  
Author(s):  
Henrik Franzyk ◽  
Morten Meldal ◽  
Hans Paulsen ◽  
Klaus Bock
Keyword(s):  
Amino Acid ◽  
Solid Phase ◽  
Building Blocks

scholarly journals Synthesis of glycosylated β3-homo-threonine conjugates for mucin-like glycopeptide antigen analogues

2010 ◽  
Vol 6 ◽  
Author(s):  
Florian Karch ◽  
Anja Hoffmann-Röder
Keyword(s):  
Amino Acid ◽  
Cancer Vaccines ◽  
Solid Phase ◽  
Building Blocks ◽  
Repeat Sequence ◽  
Amino Acid Derivative ◽  
Tandem Repeat Sequence ◽  
Important Target ◽  
Anti Cancer ◽  
Model Structures

Glycopeptides from the mucin family decorated with tumour-associated carbohydrate antigens (TACA) have proven to be important target structures for the development of molecularly defined anti-cancer vaccines. The strategic incorporation of β-amino acid building blocks into such mucin-type sequences offers the potential to create pseudo-glycopeptide antigens with improved bioavailability for tumour immunotherapy. Towards this end, TN and TF antigen conjugates O-glycosidically linked to Fmoc-β3-homo-threonine were prepared in good yield via Arndt–Eistert homologation of the corresponding glycosyl α-amino acid derivative. By incorporation of TN-Fmoc-β3hThr conjugate into the 20 amino acid tandem repeat sequence of MUC1 using sequential solid-phase glycopeptide synthesis, a first example of a mixed α/β-hybrid glycopeptide building block was obtained. The latter is of interest for the development of novel glycoconjugate mimics and model structures for anti-cancer vaccines with increased biological half-life.

Principles and Practice of Solid-Phase Peptide Synthesis

2002 ◽  
Author(s):  
Gregg B. Fields ◽  
Janelle L Lauer-Fields
Keyword(s):  
Amino Acid ◽  
Chemical Synthesis ◽  
Protease Inhibitors ◽  
Solid Phase ◽  
Building Blocks ◽  
Pharmaceutical Products ◽  
New Drugs ◽  
Side Chain ◽  
Amino Acid Residues ◽  
Functional Roles

Peptides play key structural and functional roles in biochemistry, pharmacology, and neurobiology, and are important probes for research in enzymology, immunology, and molecular biology. The amino acid building blocks can be among the 20 genetically encoded L-residues, or else unusual ones, and the sequences can be linear, cyclic, or branched. It follows that rapid, efficient, and reliable methodology for the chemical synthesis of these molecules is of utmost interest. A number of synthetic peptides are significant commercial or pharmaceutical products, ranging from the sweet dipeptide L-Asp-L-Phe-OMe (aspartame) to clinically used hormones such as oxytocin, adrenocorticotropic hormone, calcitonin, and gonadotropin releasing hormone (GnRH) super-agonists. Synthesis can lead to potent and selective new drugs by judicious substitutions that change functional groups and/or conformations of the parent peptide. These include introduction of N- or C-alkyl substituents, unnatural or D-amino acids, side-chain modifications including sulfate or phosphate groups or carbohydrate moieties, and constraints such as disulfide bridges between half-cystines or side-chain lactams between Lys and Asp or Glu. Commercially important products that evolved from such studies include protease inhibitors, such as captopril and other angiotensin converting enzyme (ACE) inhibitors, peptidomimetic HIV protease inhibitors, and the somatostatin analog lanreotide. Most of the biologically or medicinally important peptides which are the targets for useful structure-function studies by chemical synthesis comprise under 50 amino acid residues, but occasionally a synthetic approach can lead to important conclusions about small proteins (full or domains) in the 100-200 residue size range. Methods for synthesizing peptides are divided conveniently into two categories: solution (classical) and solid-phase pep tide synthesis (SPPS). The classical methods have evolved since the beginning of the twentieth century, and they are described amply in several reviews and books (Wünsch, 1974; Finn and Hofmann, 1976; Bodanszky and Bodanszky, 1984; Goodman et al, 2001). The solid-phase alternative was conceived and elaborated by R. B. Merrifield beginning in 1959, and has also been covered comprehensively (Erickson and Merrifield, 1976; Birr, 1978; Barany and Merrifield, 1979; Stewart and Young, 1984; Merrifield, 1986; Barany et al., 1987, 1988; Kent, 1988; Atherton and Sheppard, 1989; Fields and Noble, 1990; Barany and Albericio, 1991; Fields et al., 1992; Gutte, 1995; Fields, 1997; Lloyd-Williams et al., 1997; Chan and White, 2000; Kates and Albericio, 2000).

Caged Phospho-Amino Acid Building Blocks for Solid-Phase Peptide Synthesis

2003 ◽  
Vol 68 (17) ◽  
pp. 6795-6798 ◽  
Author(s):  
Deborah M. Rothman ◽  
M. Eugenio Vazquez ◽  
Elizabeth M. Vogel ◽  
Barbara Imperiali
Keyword(s):  
Amino Acid ◽  
Peptide Synthesis ◽  
Solid Phase ◽  
Solid Phase Peptide Synthesis ◽  
Building Blocks

scholarly journals Synthesis of C -Glycosyl Amino Acid Building Blocks Suitable for the Solid-Phase Synthesis of Multivalent Glycopeptide Mimics

2020 ◽  
Author(s):  
Niels R. M. Reintjens ◽  
Tony S. Koemans ◽  
Nick Zilverschoon ◽  
Riccardo Castelli ◽  
Robert A. Cordfunke ◽  
...  
Keyword(s):  
Amino Acid ◽  
Solid Phase Synthesis ◽  
Solid Phase ◽  
Building Blocks ◽  
Phase Synthesis

Synthesis of Trifluoromethyl Ketone Containing Amino Acid Building Blocks for the Preparation of Peptide-Based Histone Deacetylase (HDAC) Inhibitors

Synthesis ◽  
2018 ◽  
Vol 50 (20) ◽  
pp. 4037-4046 ◽  
Author(s):  
Christian Olsen ◽  
Carlos Moreno-Yruela
Keyword(s):  
Amino Acid ◽  
Histone Deacetylase ◽  
Solid Phase ◽  
Solid Phase Peptide Synthesis ◽  
Aqueous Media ◽  
Hdac Inhibitors ◽  
Building Blocks ◽  
Enantiomerically Pure ◽  
Trifluoromethyl Ketones ◽  
Class Iia Hdacs

Trifluoromethyl ketones (TFMKs) are electrophilic moieties which hydrate readily in aqueous media to give geminal diols. This ability has been exploited for the development of histone deacetylase (HDAC) inhibitors, because HDAC enzymes contain a Zn2+ ion which may be chelated by this functionality. Interestingly, TFMKs are exceptional Zn2+-binding groups for targeting the intriguing class IIa HDAC isozymes, involved in transcription factor recruitment and gene regulation. Here, we have developed a scalable and inexpensive synthetic procedure for preparation of the enantiomerically pure TFMK-containing amino acid building block (S)-2-amino-9,9,9-trifluoro-8-oxononanoic acid (Atona). In addition, we propose a protecting group strategy applicable to automated solid-phase peptide synthesis and demonstrate the ability of Atona-containing peptides to inhibit the enzymatic activity of class IIa HDACs with nanomolar potency. We envision that this synthesis will motivate the further development of peptide-based probes for the study of class IIa HDACs.

scholarly journals Antifreeze glycopeptide diastereomers

2012 ◽  
Vol 8 ◽  
pp. 1657-1667 ◽  
Author(s):  
Lilly Nagel ◽  
Carsten Budke ◽  
Axel Dreyer ◽  
Thomas Koop ◽  
Norbert Sewald
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Solid Phase ◽  
Solid Phase Peptide Synthesis ◽  
Antarctic Fish ◽  
Building Blocks ◽  
The Body ◽  
Ice Recrystallization ◽  
Harsh Conditions ◽  
Antifreeze Activity

Antifreeze glycopeptides (AFGPs) are a special class of biological antifreeze agents, which possess the property to inhibit ice growth in the body fluids of arctic and antarctic fish and, thus, enable life under these harsh conditions. AFGPs are composed of 4–55 tripeptide units -Ala-Ala-Thr- glycosylated at the threonine side chains. Despite the structural homology among all the fish species, divergence regarding the composition of the amino acids occurs in peptides from natural sources. Although AFGPs were discovered in the early 1960s, the adsorption mechanism of these macromolecules to the surface of the ice crystals has not yet been fully elucidated. Two AFGP diastereomers containing different amino acid configurations were synthesized to study the influence of amino acid stereochemistry on conformation and antifreeze activity. For this purpose, peptides containing monosaccharide-substituted allo-L- and D-threonine building blocks were assembled by solid-phase peptide synthesis (SPPS). The retro-inverso AFGP analogue contained all amino acids in D-configuration, while the allo-L-diastereomer was composed of L-amino acids, like native AFGPs, with replacement of L-threonine by its allo-L-diastereomer. Both glycopeptides were analyzed regarding their conformational properties, by circular dichroism (CD), and their ability to inhibit ice recrystallization in microphysical experiments.

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