Oxyazapeptides: Synthesis, Structure Determination, and Conformational Analysis

Abstract

Herein we report the synthesis, X-ray structure determination, and conformational analysis of a novel class of heteroatom-modified peptidomimetics, which we shall call "oxyazapeptides". Substituting the typical native N-C(α) bond with an O-N(α) bond creates a completely new, previously unknown family of peptidomimetics, which are hydrolytically stable and display very interesting conformational behavior. Force field calculations revealed that the barrier to rotation around the O-N(α) bond in oxyazapeptides is five times lower than that around the N-N(α) bond in azapeptides. Also, conformational analysis supported by X-ray suggests that the oxyaza moiety can effectively induce β-turns, which can make the newly discovered oxyazapeptide scaffold a useful tool for drug discovery and for design of biologics.

Synthesis, Anticonvulsant Activity and Cytotoxicity of Novel Valproic Acid Derivatives

“…The carboxylic group of valproic acid 1 was activated by treating with benzotriazole 2 in presence of thionylchloride in dichloromethane [16]. The activated vaproic acid 3 was treated with hydrazine hydrate 4 in diethyl ether to yield the hydrazide of valproic acid 5.…”

Long‐Range Chemical Ligation from N→N Acyl Migrations in Tryptophan Peptides via Cyclic Transition States of 10‐ to 18‐Members

“…The starting isotetrapeptides 14 a – d for the N→N acyl transfer via a 13‐membered TS were prepared by a straightforward coupling reaction. N ‐Acyl benzotriazoles are advantageous reagents to construct peptides, peptidomimetics, and peptide conjugates 32–34. Compound 4 and four different Boc‐protected dipeptide benzotriazolides 12 a – d were first coupled in MeCN/DIPEA to afford the Boc‐protected isotetrapeptides 13 a – d .…”

“…N-Acyl benzotriazoles are advantageous reagents to construct peptides, peptidomimetics, and peptide conjugates. [32][33][34] Compound 4 and four different Boc-protected dipeptide benzotriazolides 12 a-d were first coupled in MeCN/ DIPEA to afford the Boc-protected isotetrapeptides 13 a-d. No chromatography was needed, and compounds 13 were purified by acidic and basic workups. Boc deprotection of the Trpcontaining isotetrapeptides in 4 n HCl/dioxane afforded the Scheme 1.…”

A Review on Azapeptides: The Promising Peptidomimetics

“…These features make oxyazapeptides as useful tools for drug discovery and design of biologics (Fig. 5) [37].…”