3 years ago

Conformational properties of ascydiacyclamide analogues with cyclic α-amino acids instead of oxazoline residues

Conformational properties of ascydiacyclamide analogues with cyclic α-amino acids instead of oxazoline residues
Ascidiacyclamide [ASC, cyclo(-Ile-oxazoline-D-Val-thiazole-)2] is a cyclic octapeptide isolated from tunicates. We designed ASC analogues [cyclo(-Ile-Xxx-D-Val-thiazole-)2] in which Pro or a homologue was substituted for oxazoline: [Pro]ASC (Xxx: proline), [Aze]ASC (Xxx: (S)-Azetidine-2-carboxylic acid), [Pip]ASC (Xxx: (S)-Piperidine-2-carboxylic acid) and [ΔPro]ASC (Xxx: (S)-3-pyrroline-2-carboxylic acid) to explore their potential to serve as substitutes for the oxazoline ring. The conformations of these analogues were examined using X-ray diffraction, 1H NMR and CD spectroscopy. In both the crystal and solution states, the conformations of [Pro]ASC, [Aze]ASC and [ΔPro]ASC were novel square structures having two trans imide bonds and stabilized by two intramolecular hydrogen bonds. The crystal structure of [Pip]ASC was a folded conformation with cis and trans imide bonds. Three isomers (cc, ct and tt) were present in a solution of [Pip]ASC. From crystal structures, the degree of puckering in the side chains of Pro and its homologues was estimated to be in the order Pip > Pro > Aze > ΔPro. [Pro]ASC and [Pip]ASC showed strong cytotoxicity, but [Aze]ASC and [ΔPro]ASC showed no cytotoxicity. Among the four analogues, there is consistency between the prolyl ring puckering and cytotoxicity, but not between the peptide backbone structure and cytotoxicity.

Publisher URL: www.sciencedirect.com/science

DOI: S0968089617318266

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