Rotaxane‐Based Propeptides: Protection and Enzymatic Release of a Bioactive Pentapeptide

Abstract

Schützender Ring: Das [2]Rotaxan 1 kann ein bioaktives Pentapeptid schützen und selektiv freisetzen. Der Makrocyclus des Rotaxans stabilisiert das empfindliche Peptid sowohl gegen einzelne Peptidasen als auch gegen eine Enzymmischung aus Humanplasma. Die durch Glycosidase katalysierte Abspaltung einer Kohlenhydrat‐Endgruppe, die im Rotaxan als Stopper wirkt, führt zur Freisetzung des Peptids (siehe Bild).

A Rigid Helical Peptide Axle for a [2]Rotaxane Molecular Machine

“…The X-ray diffraction structures of the two resulting highly crystalline, peptido [2]rotaxanes (Figure 1 and see the Supporting Information) show that the fumardiamide-diethoxy moiety is an excellent station for the chair conformation of the aromatic tetramide ring, [7] despite the proximity of the bulky Aib residues or -(Aib) 4 -homopeptide helices. [8] The ring is held in place by two sets of hydrogen bonds from the two NH groups of each of its two isophthaldiamide moieties to each of the two double-acceptor fumardiamide carbonyl groups.…”

“…Moreover, in the -(Aib) 4 rotaxane the regularity of the two incipient 3 10 -helices (one right handed, the other left handed), including the presence of two intramolecular i ! i + 3 C=O···HÀN hydrogen bonds, [5] is not disturbed by the formation of the macrocycle.…”

“…Whereas the NH group of each of the two amidoethoxy linkers forms an intramolecular hydrogen bond with the urethane Fmoc-Aib carbonyl group (C 10 pseudocyclic struc- ture) in the Aib rotaxane, this same NH group in the -(Aib) 4 rotaxane is hydrogen bonded to the Aib(2) carbonyl group to afford a C 13 pseudocyclic structure. Moreover, in the -(Aib) 4 rotaxane the regularity of the two incipient 3 10 -helices (one right handed, the other left handed), including the presence of two intramolecular i !…”

“…[3] More recently, the Leigh research group described a rotaxane in which the wheel is able to protect a bioactive pentapeptide axle from peptidase-catalyzed hydrolysis. [4] We are currently investigating the synthesis and properties of a new set of symmetrical and nonsymmetrical peptido[2]rotaxanes with amino acid repeating units (oligopeptide systems) in their axles. Herein we describe our results on a [2]rotaxane shuttle in which the longest part of the axle is a rigid helical peptide, which was planned to act as a track for the reversible motion of a tetramide macrocyclic wheel.…”

“…As a first step in this study, we chose two symmetrical axles, each characterized by either two a-aminoisobutyric acid (Aib) residues or by two -(Aib) 4 -homopeptide ester sequences; the latter sequence is known to generate incipient 3 10 -helices, [5a,b] that is, secondary structures stabilized by two intramolecular, consecutive i ! i + 3 C = O···H À N hydrogen bonds.…”