生物化学技术

The side chain groups of amino acid residues in polypeptide hormones, neurotransmitters, growth factors, substrates, antigens, and other bioactive peptides have been demonstrated to be extremely important pharmacophores for receptor/acceptor binding and for signal transd ...

Oligopeptides containing an oxirane ring have recently been identified as inhibitors of a variety of proteases (1–3). These peptidomimetics have the potential to coordinate with metal present in the active site and, after nucleophilic ring opening, irreversibly blocking the enzyme. ...

Lactam-bridged dipeptides are useful tools for the introduction of conformational constraint in higher peptides. General methods have been devised for the synthesis of dipeptides having five-, six-, and seven-membered ring constraints (1,2). This chapter will focus on four synthet ...

Poor oral bioavailability, low metabolic stability towards proteolysis and rapid excretion via both liver and kidneys displayed by innumerable peptides of potential therapeutic value has generated an intensive search for peptidomimics (1–2). A possible approach of such nonpep ...

We have been examining synthetic approaches to conformationally restricted peptide building blocks that would allow for the construction of a variety of possible structures in a straight-forward, general way (1). To date, this effort has focused on developing the chemistry needed to ra ...

This chapter describes the synthetic procedures leading to ether dipeptide isosteres of the Phe-ψ-spiro-Cx (9a–9e, Fig. 1) and Phe-ψ-Allylglycine (13, Fig. 2). Development of methods which lead to mimetics of amide bonds is central to the conversion of peptide leads into pharmaceutically v ...

The endo aryl-aryl and aryl-alkyl ether bonds exist in a number of biologically important macrocyclic natural products, such as vancomycin family glycopeptide antibiotics (1–3), antitumor series RA I-XIV (4), K-13 (5), OF4949 (6), piperazinomycin (7), cyclopeptide alkaloids (8,9), non ...

The concept of topographic design of peptide neurotransmitters and hormones was pioneered by Hruby (1,2). When the design involved primarily constraint of the side chains of a peptide that has a well-defined backbone conformation, the term “topographic design on a stable template” was pro ...

Unnatural and naturally occurring nonproteinogenic α-amino acids have become important building blocks for the synthesis of biologically active peptides and peptidomimetic drug molecules. The asymmetric synthesis of α-amino acids has therefore become quite important as an ...

This chapter focuses on the isosteric replacement of peptide bonds with three different types of heterocyclic ring systems (1); 1,2,4-oxadiazole (2), 1,3,4-oxadiazole (3), and 1,2,4-triazole rings (4–6). The ring systems are similar in size and shape but show variations in aromatic, electro ...

Replacement of the amide bond in the peptide backbone can improve the activity, stability, or bioavailability of the resultant unnatural peptide (1). Amide bond surrogates cannot only impart peptidase resistance, but can also facilitate conformational control of the target peptide. ...

Replacement of key structural or binding elements of a peptide lead with nonpeptide components can improve affinity and metabolic stability (1–5). Such a strategy was successfully applied to the generation of potent, cell-permeable inhibitors of Ras famesyltransferase (FTase) (6 ...

The use of cyclopropanes as a conformationally restricted subunits in biological systems has been the subject of intense study by our group and others (1–10). Our recent efforts have focused on the use of 1, 2, 3-trisubstituted cyclopropanes as novel or bond replacements in pseudopeptides to re ...

Proline occupies a special role among those amino acids incorporated into peptides and proteins by the normal ribosomal pathways, since it is the only residue that leads to an N-alkyl amide bond. In peptide natural products that often have special biosynthetic pathways or unusual posttran ...

The use of substituted cyclopropanes as conformationally constrained peptidomimetics has received considerable attention recently (1–6). The efforts from our laboratory in this area have focused on the use 1,2,3-trisubstituted cyclopropanes as novel isosteric replaceme ...

The dipeptidic dihydroxyethylene isostere (27, 3R, 4R, 5S)-5-tert-butyloxy-carbonylamino-3,4-dihydroxy-2-isopropyl-3,4-O,O-isoprop-ylidene-6-cyclohexyl-hexanoic acid, 15, is a representative building block of an important class of unnatural dipeptide mimic ...

In an effort to produce renm mhibttory peptides, the preparation of (2S,4S,5S)-5-(t-Butoxycarbonylamino)-4-(t-butyldimethylsilyloxy)-2-isopropyl-7-methyl octanotc acid, 15, was carried out (1). This pseudo-dipeptide was used to replace combinattons of leucme coupled wi ...

This chapter presents procedures for the synthesis of α-vinyl amino acids, in which the usual α-proton is replaced by an unsubstituted vinyl group (Fig. 1). The parent member of this family, α-vinylglycine (R≠H), is a natural product (1,2) and acts as a suicide substrate for a number of PLP-dependent enz ...

Stereochemicaly well-defined 3-, 4-, and 5-monosubstituted prolines can play an important role as probes in search of potent neuroexitatory agents or in the construction of conformationally constrained peptides. Mimicking distinct conformations of excitatory amino acids may ...

2,3-Methanoamino acids resemble protein amino acids. The only difference between these groups of compounds is that the former have one additional carbon which spans the α- and β atoms (Fig. 1). This cyclopropane ring constraint of 2,3-methanoamino acids allows four side chain orientations; ...