Going Out on a Limb: Delineating The Effects of β-Branching, N-Methylation, and Side Chain Size on the Passive Permeability, Solubility, and Flexibility of Sanguinamide A Analogues
Going Out on a Limb: Delineating The Effects of β-Branching, N-Methylation, and Side Chain Size on the Passive Permeability, Solubility, and Flexibility of Sanguinamide A Analogues
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DOI：
10.1021/acs.jmedchem.5b00919
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发表时间：
2015-09-24
影响因子：
7.3
通讯作者：
Lokey, R. Scott
中科院分区：
文献类型：
--
作者：
Bockus, Andrew T.;Schwochert, Joshua A.;Lokey, R. Scott
众所周知，分子内氢键和N-甲基化在环肽的被动渗透性中起着重要作用，但其他结构特征的研究较少。最近对环状七肽血酰胺A的口服生物利用度的研究提出了一个问题，即通过β-分支对极性基团进行空间位阻是否是环状肽渗透性优化的有效但尚未开发的工具。我们报告了17个血酰胺A类似物的结构，旨在测试β-分支，N-甲基化和侧链大小对被动膜渗透性和水溶性的相对贡献。我们证明，β-分支的渗透性的影响相比，暴露的NH基团的脂肪族碳数和N-甲基化的影响很小。我们强调了一个新的N-甲基化类似物的血酰胺A与Leu取代的位置2，表现出溶剂依赖性的灵活性和改善的渗透性超过天然产品。
It is well established that intramolecular hydrogen bonding and N-methylation play important roles in the passive permeability of cyclic peptides, but other structural features have been explored less intensively. Recent studies on the oral bioavailability of the cyclic heptapeptide sanguinamide A have raised the question of whether steric occlusion of polar groups via beta-branching is an effective, yet untapped, tool in cyclic peptide permeability optimization. We report the structures of 17 sanguinamide A analogues designed to test the relative contributions of beta-branching, N-methylation, and side chain size to passive membrane permeability and aqueous solubility. We demonstrate that beta-branching has little effect on permeability compared to the effects of aliphatic carbon count and N-methylation of exposed NH groups. We highlight a new N-methylated analogue of sanguinamide A with a Leu substitution at position 2 that exhibits solvent-dependent flexibility and improved permeability over that of the natural product.