Davenport Research Laboratories, Department of Chemistry , University of Toronto , 80 St. George Street , Toronto , Ontario M5S 3H6 , Canada.
J Am Chem Soc. 2018 Jul 18;140(28):8763-8770. doi: 10.1021/jacs.8b04412. Epub 2018 Jul 3.
Synthetic methods that provide control over macrocycle conformation represent valuable tools for the discovery of bioactive molecules. Incorporation of heterocycles into cyclic peptides may offer a way to stabilize their solution conformations. Herein, we used N-(isocyanimino)triphenylphosphorane (Pinc) to install an oxadiazole ring and an endocyclic amine into peptide macrocycles. To elucidate the conformational effect of this constellation of functionalities, we performed synthesis, variable temperature NMR analysis, and NOE-based molecular dynamics simulation of a range of macrocycles in DMSO. As part of this study, we conducted experiments to compare macrocycle conformation in aqueous and DMSO solutions. The obtained solution structures suggest that the reduced amide bond/heterocycle (RAH) motif can stabilize macrocycle conformations in both water and DMSO, which addresses an enduring challenge in molecular design. The conformational effect of the RAH was used in an effort to mimic the biologically relevant secondary structure of MAdCAM-1. This resulted in the discovery of a novel αβ integrin antagonist.
合成方法可以控制大环构象，这是发现生物活性分子的有价值的工具。将杂环并入环状肽中可能是稳定其溶液构象的一种方法。在此，我们使用 N-(异氰基)三苯基膦（Pinc）在肽大环中安装噁二唑环和内环胺。为了阐明这种功能组合的构象效应，我们在 DMSO 中进行了一系列大环的合成、变温 NMR 分析和基于 NOE 的分子动力学模拟。作为这项研究的一部分，我们进行了实验来比较大环在水相和 DMSO 溶液中的构象。所得到的溶液结构表明，酰胺键/杂环（RAH）基序可以在水和 DMSO 中稳定大环构象，这解决了分子设计中的一个长期挑战。RAH 的构象效应被用于模拟 MAdCAM-1 的生物学相关二级结构。这导致了一种新型的 αβ 整合素拮抗剂的发现。
