Hitting a Moving Target: How Does an N-Methyl Group Impact Biological Activity?

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• 作者：Yen Chin Koay ; Nicole L. Richardson ; Samantha S. Zaiter ; Jessica Kho ; Sheena Y. Nguyen ; Daniel H. Tran ; Ka Wai Lee ; Laura K. Buckton and Prof. Shelli R. McAlpine
• 关键词：antitumor agents ; cytotoxicity ; heat-shock protein 90 ; protein folding ; unfolded protein response
• 刊名：ChemMedChem
• 出版年：2016
• 出版时间：April 19, 2016
• 年：2016
• 卷：11
• 期：8
• 页码：881-892
• 全文大小：1670K
• ISSN：1860-7187

文摘

Macrocycles have several advantages over small-molecule drugs when it comes to addressing specific protein–protein interactions as therapeutic targets. Herein we report the synthesis of seven new cyclic peptide molecules and their biological activity. These macrocycles were designed to understand how moving an N-methyl moiety around the peptide backbone impacts biological activity. Because the lead non-methylated structure inhibits the oncogenic regulator heat-shock protein 90 (Hsp90), two of the most potent analogues were evaluated for their Hsp90 inhibitory activity. We show that incorporating an N-methyl moiety controls the conformation of the macrocycle, which dramatically impacts cytotoxicity and binding affinity for Hsp90. Thus, the placement of an N-methylated amino acid within a macrocycle generates an unpredictable change to the compound's conformation and hence biological activity.