We herein report the first thorough analysis of the structure–permeability relationship of semipeptidic macrocycles. In total, 47 macrocycles were synthesized using a hybrid solid-phase/solution strategy, and then their passive and cellular permeability was assessed using the parallel artificial membrane permeability assay (PAMPA) and Caco-2 assay, respectively. The results indicate that semipeptidic macrocycles generally possess high passive permeability based on the PAMPA, yet their cellular permeability is governed by efflux, as reported in the Caco-2 assay. Structural variations led to tractable structure–permeability and structure–efflux relationships, wherein the linker length, stereoinversion, N-methylation, and peptoids site-specifically impact the permeability and efflux. Extensive nuclear magnetic resonance, molecular dynamics, and ensemble-based three-dimensional polar surface area (3D-PSA) studies showed that ensemble-based 3D-PSA is a good predictor of passive permeability.

中文翻译：

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半肽大环化合物的结构-渗透率关系-了解和优化被动渗透率和外流比。

我们在此报告了对半肽大环化合物的结构-渗透率关系的首次全面分析。总共使用混合固相/溶液策略合成了47个大环，然后分别使用平行人工膜通透性测定（PAMPA）和Caco-2测定来评估它们的被动和细胞通透性。结果表明，半肽大环化合物通常具有基于PAMPA的高被动通透性，但其细胞通透性却由外排决定，如Caco-2分析所示。结构变化导致易处理的结构-渗透率和结构-流出关系，其中接头长度，立体反转，N-甲基化和类肽特异性地影响渗透率和流出。广泛的核磁共振，分子动力学，