Peptides, fixed cyclic

Other examples of Ugi reactions combined with RCM have been described in the literature. Hebach and Kazmaier reported the synthesis of conformationally fixed cyclic peptides [70] and Beck and Domling synthesized biaryl-containing natural product-like macrocycles using this method [41]. The same group also reported combination of Passerini and Horner-Wadsworth-Emmons reactions to obtain butenolides [67] and another variation for the combinatorial synthesis of thiazoles [69]. 

Hebach C, Kazmaier U (2003) Via Ugi reactions to conformationally fixed cyclic peptides. Chem Commun 5 596-597... 

Depending on the structure calculation program used, special covalent bonds such as disulfide bridges or cyclic peptide bonds have to be enforced by distance constraints. Disulfide bridges may be fixed by restraining the distance between the two sulfur atoms to 2.0-2.1 A and the two distances between the Cb and the sulfur atoms of different residues to 3.0-3.1 A [7]. 

Suggested preferred conformations can be fixed by cyclization. Cystine has been used to obtain cyclic analogues of Org 2766 viz. H-Cys-Glu-His-Cys-D-Lys-Phe-OH, H-Cys-Ala-Ala-Cys-D-Lys--Phe-OH and H-Cys-Ala-Ala-Phe-D-Lys-Cys-OH (patent application 0052028 of Roussel-UcIaf), and the peptides were tested for activity in the pole-jumping test. Unfortunately, one cannot conclude from their data if cyclization has resulted in an increase or decrease in activity since no reference peptide has been included to compare potencies. In the literature cyclization of [Lys ]ACTH--(5-10) (the COOH group of Gly with the 6-NH2 function of Lys ) has been reported the resulting peptide was inactive in steroidogenesis (61). Increase of the ring size with three atoms (a Gly residue), however, resulted in a peptide that was more active... 

The P-tetralin amino acid induces the a-helical conformation by fixing the torsional angles along the peptide backbone at about -60° (< >) and -50° ( p).109 P-Tetralin amino acids may be regarded as cyclic-constrained phenylalanine analogues. As shown in Section II.A, this class of unnatural amino acids is known to stabilize distinct conformations in peptides since the two substituents at the a-cen-ter restrict the available conformational space. Cyclic a,a-dialkylated glycines and a-substituted alanines preferentially adopt a-helical conformations.205... 

Notice in Table 24-2 how proline is different from the other standard amino acids. Its amino group is fixed in a ring with its a carbon atom. This cyclic structure lends additional strength and rigidity to proline-containing peptides. 

The Ghadiri group used metathesis to "fix a system formed by self-assembly. In this cyclic peptide system, the dimer is formed by complimentary hydrogen bonds [33], after which the metathesis reaction "stitches the two halves together to form a stable structure (Eq. 6.12). 

While the previous studies showed that substrate peptides were not found in p turn conformations in solution, they cannot rule out binding of the peptide to the enzyme in this conformation. In order to determine whether this was the case, peptides were synthesized which were constrained into a p turn (79). In the cyclic hexapeptides 2a and 2b, the proline-D-amino acid dipeptide forms a type II p turn. This locks the remaining residues into a type I p turn with the asparagine fixed into either the (i) or (i+1) position of this turn. One and two dimensional NMR confirmed that these peptides were in the predicted conformations with all the predicted NOE connectivities and with the expected intramolecular hydrogen bonding (79). 

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