Chung Benjamin K W, White Christopher J, Scully Conor C G, Yudin Andrei K
Davenport Research Laboratories , Department of Chemistry , The University of Toronto , 80 St. George Street , Toronto , Ontario M5S 3H6 , Canada . Email:
Chem Sci. 2016 Nov 1;7(11):6662-6668. doi: 10.1039/c6sc01687a. Epub 2016 Jun 30.
Among the smallest of the macrocyclic peptides, 12- and 13-membered cyclic tetrapeptides are particularly noteworthy because they exhibit a broad spectrum of biological activities due to their innate capacity to mimic β-turns in proteins. In this report, we demonstrate that aziridine-containing cyclic tetrapeptides offer a platform to interrogate the conformational properties of tetrapeptides. We show that aziridine ring-opening of 12-membered cyclic tetrapeptides yields exclusively 13-membered αβ macrocycles, regardless of peptide sequence, nucleophile, aziridine β-carbon substitution, or stereochemistry. NMR and computational studies on two related aziridine-containing cyclic tetrapeptides revealed that the amide conformations of their -acyl aziridines are similar, and are likely the determinant of the observed ring-opening regioselectivity. Interestingly, some of the resulting 13-membered αβ macrocycles were found to be conformationally heterogeneous. This study on the reactivity and conformational control of aziridine-containing cyclic tetrapeptides provides useful insight on the design and development of macrocyclic therapeutics.
在最小的大环肽中，12元和13元环四肽尤其值得关注，因为它们由于具有模拟蛋白质中β-转角的内在能力而展现出广泛的生物活性。在本报告中，我们证明含氮丙啶的环四肽为探究四肽的构象性质提供了一个平台。我们表明，无论肽序列、亲核试剂、氮丙啶β-碳取代或立体化学如何，12元环四肽的氮丙啶开环仅产生13元αβ大环。对两种相关的含氮丙啶环四肽的核磁共振和计算研究表明，它们的酰基氮丙啶的酰胺构象相似，并且可能是观察到的开环区域选择性的决定因素。有趣的是，发现一些所得的13元αβ大环在构象上是异质的。这项关于含氮丙啶环四肽的反应性和构象控制的研究为大环治疗药物的设计和开发提供了有用的见解。
