The acid lability of aliphatic ketals, which often serve as protection groups for 1,2-diols, is influenced by their local structural environment. The acetonide of the protected amino acid cis-dihydroxyproline (Dyp) is a typical protecting group cleavable by traces of TFA. The tricyclic acetonide of the dipeptide d-Hot═Tap is resistant to TFA and thus can serve as a bioorthogonal modification of bioactive peptides. With the aim of improving antimicrobial activity and hemolytic properties, we use these reactivity differences to scale the membrane affinity of the decapeptide Gramicidin S cyclo(d-Phe-Pro-Val-Orn-Leu-)₂ (GS). The cis-dihydroxylated amino acids are used to increase the polarity of GS or obversely decrease the polarity by stereoselective ketal formation with an aliphatic ketone. While Dyp (GS mimetic 15) has only minimal influence on the biological properties of GS, d-Hot═Tap at the position of d-Phe1-Pro2 eradicates the biological activity (GS mimetic 16). The acid-stable ketals 17–19 are bioorthogonal modifications which reconstitute the biological activity of GS. We describe an improved synthesis of orthogonally protected Fmoc-Dyp-acetonide (9) and of several Fmoc-d-Hot═Tap-ketals for solid-phase peptide synthesis.

中文翻译：

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通过二羟基化或缩酮形成结垢垢霉菌素S的两亲特性和抗菌活性

脂肪族缩酮的酸不稳定性通常受1,2-二醇保护基的影响，受其局部结构环境的影响。被保护的氨基酸顺式-二羟基脯氨酸（Dyp）的丙酮化物是典型的可被痕量的TFA裂解的保护基。二肽d- Hot═Tap的三环丙酮化物对TFA具有抗性，因此可以用作生物活性肽的生物正交修饰。为了提高抗菌活性和溶血特性，我们使用这些反应性差异来缩放十肽格米星素S环（d -Phe-Pro-Val-Orn-Leu-）₂（GS）的膜亲和力。该顺-二羟基化氨基酸用于通过与脂肪族酮的立体选择性缩酮形成来增加GS的极性或相反地降低极性。虽然Dyp（GS模拟物15）对GS的生物学特性影响很小，但d- Phe1 -Pro2位置的d - Hot═Tap消除了生物活性（GS模拟物16）。酸稳定的缩酮17 – 19是生物正交修饰，可重构GS的生物活性。我们描述正交保护的Fmoc-DYP丙酮（的改进的合成9）和几个的Fmoc- d-Hot═Tap-缩酮，用于固相肽合成。