Conformational properties of ascydiacyclamide analogues with cyclic α-amino acids instead of oxazoline residues. Issue 24 (15th December 2017)

• Record Type: Journal Article
• Authors: Asano, Akiko; Numata, Shohei; Yamada, Takeshi; Minoura, Katsuhiko; Doi, Mitsunobu
• Is Part Of: Bioorganic & medicinal chemistry. Volume 25:Issue 24(2017)
• Page Start: 6554
• Page End: 6562
• Publication Date: 2017-12-15
• Subjects: Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2017.10.029
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: 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, 1 H 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.