Helix-Forming Propensity of Aliphatic Urea Oligomers Incorporating Noncanonical Residue Substitution Patterns

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• 作者：Nagendar Pendem ; C茅line Douat ; Paul Claudon ; Michel Laguerre ; Sabine Castano ; Bernard Desbat ; Dominique Cavagnat ; Eric Ennifar ; Brice Kauffmann ; Gilles Guichard
• 刊名：The Journal of the American Chemical Society
• 出版年：2013
• 出版时间：March 27, 2013
• 年：2013
• 卷：135
• 期：12
• 页码：4884-4892
• 全文大小：555K
• 年卷期：v.135,no.12(March 27, 2013)
• ISSN：1520-5126

文摘

Aliphatic N,N鈥?linked oligoureas are peptidomimetic foldamers that adopt a well-defined helical secondary structure stabilized by a collection of remote three-center H-bonds closing 12- and 14-membered pseudorings. Delineating the rules that govern helix formation depending on the nature of constituent units is of practical utility if one aims to utilize this helical fold to place side chains in a given arrangement and elaborate functional helices. In this work, we tested whether the helix geometry is compatible with alternative substitution patterns. The central 鈭扤H鈥揅H(R)鈥揅H₂鈥揘H鈥揅O鈥?residue in a model oligourea pentamer sequence was replaced by guest units bearing various substitution patterns [e.g., 鈭扤H鈥揅H₂鈥揅H₂鈥揘H鈥揅O鈥? 鈭扤H鈥揅H₂鈥揅H(R)鈥揘H鈥揅O鈥? and 鈭扤H鈥揅H(R¹)鈥揅H(R²)鈥揘H鈥揅O鈭抅, levels of preorganization (cyclic vs acyclic residues), and stereochemistries, and the helix formation was systematically assessed. The extent of helix perturbation or stabilization was primarily monitored in solution by Fourier transform IR, NMR, and electronic circular dichroism spectroscopies. Our results indicate that although three new substitution patterns were accommodated in the 2.5-helix, the helical urea backbone in short oligomers is particularly sensitive to variations in the residue substitution pattern (position and stereochemistry). For example, the trans-1,2-diaminocyclohexane unit was experimentally found to break the helix nucleation, but the corresponding cis unit did not. Theoretical calculations helped to rationalize these results. The conformational preferences in this series of oligoureas were also studied at high resolution by X-ray structure analyses of a representative set of modified oligomers.