Proline constrained

The most common bicyclic 5-6 system with one bridgehead N-O and one extra heteroatom described in the period covered in this chapter has been the diketopiperazine derived from proline as it is present in natural products, in biologically active synthetic molecules, and has been used as starting material for the preparation of conformationally constrained peptidomimetics. The classical approach to this class of molecule is the ring closing of the dipeptide derived from proline and another amino acid via nucleophilic attack of the NH2 to the activated carboxylic group. This method has been applied several times to prepare different diketopiperazines for different uses. 

The use of an anodic amide oxidation to introduce a vinyl group to the C5 position of a proline derivative has proven to be an effective strategy for building other constrained peptidomimetics as well. For example, a variation on the approach has... 

Monoclonal antibodies raised against proline derivatives (94a) and (94b) have been used to catalyse the selenoxide. vyw-elimination reaction (95) — (97). It was reasoned that the flexible selenoxide (95) would be constrained within the low dielectric... 

In the synthesis of l,2,5-triazepine-l,5-diones, which are expected to mimic the structural features of or-peptidyl prolin-amides, the preparation of N2,N3-disubstituted derivatives 213a from the reaction of (Z)-alanine with the N2-substituted triazepines 213 resulted in lower yields. It has been reported that these fused triazepinediones could be elaborated to give constrained rir-peptidyl proline peptide mimetics of defined stereochemistry and sequence <1997J(P1)2297>. 

Bunuel, E. Gil, A. M. Diaz-de-Villegas, M. D. Cativiela, C. Synthesis of constrained prolines by Diels—Alder reaction using a chiral unsaturated oxazolone derived from (R)-glyceralde-hyde as starting material. Tetrahedron 2001,... 

Only the achiral glycine can readily adopt conformations different from those in the favored regions proline, because of, the ring system, is highly constrained in its conformation. 

A tendency is discernible towards specific context scaffolds and dedicated gene banks to approach particular problems (e.g. proline-rich for SH3-domains constrained scaffolds in addition to antibodies, e g. in the search for protease inhibitors or integrin competitors) as well as becoming a basic tool in protein design studies. 

The synthesis of proline containing tripeptides constrained with phenylalanine-like aziridine and dehydrophenylalanine residues was accomplished in the laboratory of J. Iqbal.These tripeptides show -turn structure in solution and are good models for studying the mechanism of HIV protease. The aziridine rings in these tripeptides were stereoselectively transformed via the Heine reaction in two steps to the corresponding dehydrophenylalanine containing tripeptides, which also prefer to form -turn structures in solution. 

Based on the findings from an alanine scan, further peptides can be synthesized in which residues involved in the receptor recognition are substituted by homologous amino acids. Interesting in this context is also the use of conformation-ally constrained analogues in which amino acid residues such as the helix breaker proline or the tum-inducing motive alanine-aminoisobutyric acid are introduced into the natural peptide sequence. 

For example, substitution with / -alkyl proline results in a W angle constrained by the syn-(l substituent around 0° while (S)-a-methyl substituted proline induces... 

Protein synthesis in the body is constrained to 20 amino acids (including the imino acid proline), but modifications made after translation greatly extend the range of side chains found in mature proteins. Reversible modifications provide opportunities for regulation of protein function. 

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