Passive Membrane Permeability of Macrocycles Can Be Controlled by Exocyclic Amide Bonds

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• 作者：Jennifer L. Hickey ; Serge Zaretsky ; Megan A. St. Denis ; Sai Kumar Chakka ; M. Monzur Morshed ; Conor C. G. Scully ; Andrew L. Roughton ; Andrei K. Yudin
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：June 9, 2016
• 年：2016
• 卷：59
• 期：11
• 页码：5368-5376
• 全文大小：400K
• 年卷期：0
• ISSN：1520-4804

文摘

We have developed a strategy for synthesizing passively permeable peptidomimetic macrocycles. The cyclization chemistry centers on using aziridine aldehydes in a multicomponent reaction with peptides and isocyanides. The linker region in the resulting product contains an exocyclic amide positioned α to the peptide backbone, an arrangement that is not found among natural amino acids. This amide provides structural rigidity within the cyclic peptidomimetic and promotes the creation of a stabilizing intramolecular hydrogen bonding network. This exocyclic control element also contributes to the increased membrane permeability exhibited by multicomponent-derived macrocycles with respect to their homodetic counterparts. The exocyclic control element is employed along with a strategic placement of N-methyl and d-amino acids to produce passively permeable peptides, which contain multiple polar residues. This strategy should be applicable in the pursuit of synthesizing therapeutically relevant macrocycles.