Effect of the powerful plasticity of the tert‐butyl side chain on the conformational equilibrium of ascidiacyclamides. (30th August 2021)

• Record Type: Journal Article
• Authors: Asano, Akiko; Nakagawa, Maki; Miyajima, Chihiro; Yasui, Mami; Minoura, Katsuhiko; Yamada, Takeshi; Doi, Mitsunobu
• Is Part Of: Journal of peptide science. Volume 27:Number 12(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-08-30
• Subjects: 1H NMR -- ascidiacyclamide -- CD spectrum -- conformational equilibrium -- crystal structure -- cytotoxicity -- Gibbs free energy -- tert‐leucine; Peptides -- Periodicals; Peptides -- Periodicals; 572.65
• DOI: 10.1002/psc.3363
• Languages: English
• ISSNs: 1075-2617

Abstract

Abstract : Ascidiacyclamide [cyclo(‐Ile 1, 5 ‐oxazoline 2, 6 ‐d ‐Val 3, 7 ‐thiazole 4, 8 ‐)2 ] is a cytotoxic cyclic peptide from ascidian. Through structural analyses using monosubstituted analogues (Xaa 1 : Ala, 2‐aminobutyric acid, Val, cyclohexylglycine, and phenylglycine), we previously demonstrated the conformational equilibrium between its square and folded forms. As the bulkiness of the Xaa 1 residue side chain was reduced, spontaneous folding was promoted, and the cytotoxicity decreased accordingly. In the present study, five disubstituted analogues in which a tert ‐leucine residue (Tle) was incorporated at the 5‐position of the abovementioned monosubstituted analogues were synthesized, after which their structures were analyzed using X‐ray diffraction, circular dichroism (CD) spectral measurements, and 1 H NMR‐based quantitative analysis. The side chains of the Tle and Ile residues are structural isomers of one another, and the Tle residue bearing the tert ‐butyl group can be expected to play a role as a building block. In fact, peptides incorporating Tle 5 exhibited much less spontaneous folding than their Ile 5 counterparts in both crystal and solution. Increases in enthalpy and entropy due to the tert ‐butyl group during the folding process resulted in increased conformational free energy (Δ G °). The powerful plasticity of the tert ‐butyl group would stabilize the square form relating with cytotoxicity. Abstract : As the bulkiness of the side chain (R) is reduced, spontaneous folding is promoted (red bars), but peptides incorporating tert ‐butyl group exhibited much less spontaneous folding (blue bars).