Synthesis of Conformationally Restricted Mimetics of -Turns and Incorporation into Desmopressin, an Analogue of the Peptide Hormone Vasopressin

Abstract

Mimetics of tripeptides adopting inverse and classical g-turn conformations have been designed and synthesized by an enantioselective approach and then incorporated in an analogue of the hormone vasopressin. In the mimetics one of the amide bonds of the g-turn has been exchanged for a Y[CH 2 O] isostere and the hydrogen bond between residues i and i2 of the turn has been replaced by a methylene bridge to give a six-membered, morpholin-3-one ring. The turn mimetics were assembled from three types of building blocks: azido epoxides, a-bromo acids and b-amino alcohols. Of these, the stereochemistry of the azido epoxide determines whether a classical or an inverse g-turn is mimicked. The key azido epoxide building blocks were prepared in six steps and approximately 40 % overall yield, whereas the a-bromo acids and b-amino alcohols were either commercially available or readily prepared from amino acids. The buildingblock approach allowed substantial variation of the side chains of the mimetics, together with complete stereocontrol, as well as use of uniform conditions for preparation of both classical and inverse g-turn mimetics. Conformational studies based on ab initio calculations and 1 H NMR spectroscopy revealed that the minimum-energy conformations of the mimetics closely resembled inverse or classical g-turns.

Synthesis and Evaluation of the β‐Turn Properties of 4‐Amino‐1,2,4,5‐tetrahydro‐2‐benzazepin‐3‐ones and of Their Spirocyclic Derivative

“…[1] In Table 2 and Figure 10, the lowest-energy conformers are given, together with the values for the different criteria. The lowest-energy conformer of Ac-(S)-Aba-Gly-NHMe (7) is not a β-turn, and the lowest-energy conformation that does adopt a turn is 14.85 kJ/mol above the minimum. Similar results were obtained for Ac-(S)-Aba-(R)-Ala-NHMe Table 2.…”

“…[1] In a β-turn, the reversal of the peptide backbone occurs over four amino acid residues in such a way that the carbonyl oxygen atom of the first residue (i) and the amide NH proton of the fourth residue (i + 3) come close in space, and in most cases are involved in an intramolecular hydrogen bridge forming a pseudoten-membered ring. [7] β-Turn mimetics can be categorized in two distinct classes: internal and external mimetics. Internal mimetics are constructed upon frameworks within the pseudo-ten-membered ring, preserving the amino acid side-chain orientations.…”

“…N-acetyl dipeptide NЈ-methylamides 5, 6, 7, 8 and 9 were prepared as mimics for the tetrapeptides [21] and their conformational properties were examined by NMR and molecular modeling to evaluate their β-turn mimicry. Analogs containing Gly as the i + 2 residue (7), N-methylated Aba 8, heterochiral (5) and homochiral sequences (6) were studied.…”

Synthesis of new chiral organosulfur donors with hydrogen bonding functionality and their first charge transfer salts

“…With a view to resolving the chirality at the stereogenic centre on a BEDT-TTF derivative in a shorter sequence we have taken an approach to deliberately prepare diastereomers which can then be separated, in this case by modification of our synthesis of the racemic BEDT-TTF derivatives bearing a functionalised acetamide side chain (-CH2CONHR). 30 Trithione 41 25 was reacted with vinylacetic acid to give the bicyclic carboxylic acid 42, which was then converted to two diastereoisomeric amides 43 and 44 by formation of the mixed anhydride with ethyl chloroformate followed by reaction with the enantiopure amine R-α-phenylethylamine.…”

Peptidomimetics and their Applications in Antifungal Drug Design

“…Some examples from the vast literature [86] in the field are peptidomimetics of vasopressin [99], oxytocin [100], LHRH [101], somatostatin and angiotensin II [102,103]. Type-III mimetics represent the idyllic peptidomimetics in that they possess novel templates which, though appearing unrelated to the original peptides, contain the necessary groups positioned on a novel nonpeptide scaffold to serve as topographical mimetics [104,105].…”