Effect of the powerful plasticity of the tert-butyl side chain on the conformational equilibrium of ascidiacyclamides,Journal of Peptide Science

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Effect of the powerful plasticity of the tert-butyl side chain on the conformational equilibrium of ascidiacyclamides
Journal of Peptide Science ( IF 1.8 ) Pub Date : 2021-08-30 , DOI: 10.1002/psc.3363
Akiko Asano ₁ , Maki Nakagawa ₁ , Chihiro Miyajima ₁ , Mami Yasui ₁ , Katsuhiko Minoura ₁ , Takeshi Yamada ₁ , Mitsunobu Doi ₁

Affiliation

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 (Xaa¹: 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 Xaa¹ 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 ¹H 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 Tle⁵ exhibited much less spontaneous folding than their Ile⁵ 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 (ΔG°). The powerful plasticity of the tert-butyl group would stabilize the square form relating with cytotoxicity.

中文翻译：

叔丁基侧链的强塑性对水生环酰胺构象平衡的影响

Ascidiacyclamide [cyclo(-Ile ^1,5 -oxazoline ^2,6 - d -Val ^3,7 -thiazole ^4,8 -) ₂ ] 是一种来自海鞘的细胞毒性环肽。通过使用单取代类似物（Xaa ¹：Ala、2-氨基丁酸、Val、环己基甘氨酸和苯基甘氨酸）的结构分析，我们之前证明了其方形和折叠形式之间的构象平衡。随着Xaa ¹残基侧链体积减小，自发折叠得到促进，细胞毒性相应降低。在本研究中，五个二取代的类似物，其中一个叔合成了在上述单取代类似物的5-位掺入-亮氨酸残基(Tle)，然后使用X射线衍射、圆二色性(CD)光谱测量和基于¹ H NMR的定量分析来分析它们的结构。Tle 和 Ile 残基的侧链是彼此的结构异构体，可以预期带有叔丁基的 Tle 残基起到结构单元的作用。事实上，结合 Tle ⁵的肽在晶体和溶液中表现出比 Ile ^{5对应物少得多的自发折叠。}由于叔叔的焓和熵增加折叠过程中的-丁基导致构象自由能（ΔG °）增加。叔丁基的强大可塑性将稳定与细胞毒性相关的方形。

更新日期：2021-11-05

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