Seven ascidiacyclamide [cyclo(–Ile–oxazoline–d‐Val–thiazole–)₂] (ASC) analogues incorporating the β‐amino acids βIle, βoxazoline, and/or d‐βVal were synthesized. We then investigated the effects of the position and number of incorporated β‐amino acids on the structure, cytotoxicity, and copper binding by these seven analogues. The structural analyses revealed that both βIle and d‐βVal favor a gauche‐type θ torsion angles, while βoxazoline favors a trans‐type θ torsion angle. Expansion of the macrocycle by incorporation of βIle or d‐βVal readily induced molecular folding. On the other hand, the incorporation of two βoxazoline residues strongly extended the peptide conformation, and the incorporation of one was sufficient for the moderate restriction important for conformational equilibrium and cytotoxicity. Despite expansion of the macrocycles, the structure‐cytotoxicity relationships were largely maintained. In studies of complexation of the analogues with Cu (II) ion, the position and number of incorporated β‐amino acids had a large impact on the structure of the metal complex and may contribute to its stabilization.

中文翻译：

---

将β-氨基酸掺入环二酰胺中：对构象，细胞毒性和与铜（II）离子的相互作用的影响。

合成了七个含有β-氨基酸βIle，β恶唑啉和/或d - βVal的ascidiacyclamide [环（-Ile-恶唑啉-d -Val-噻唑-）₂ ]（ASC）类似物。然后，我们研究了这七个类似物对β-氨基酸的位置和数量的影响，对结构，细胞毒性和铜结合的影响。结构分析表明，βIle和d -βVal均有利于gauche型θ扭转角，而β恶唑啉有利于反型θ扭转角。通过掺入βIle或d来扩大大环-βVal容易引起分子折叠。另一方面，两个β恶唑啉残基的掺入强烈地延长了肽的构象，而一个的掺入足以对构象平衡和细胞毒性重要的中等限制。尽管大环化合物扩展了，但仍保持了结构-细胞毒性的关系。在研究类似物与Cu（II）离子的络合过程中，结合的β-氨基酸的位置和数量对金属络合物的结构影响很大，并可能有助于其稳定。