Premium
Hitting a Moving Target: How Does an N ‐Methyl Group Impact Biological Activity?
Author(s) -
Koay Yen Chin,
Richardson Nicole L.,
Zaiter Samantha S.,
Kho Jessica,
Nguyen Sheena Y.,
Tran Daniel H.,
Lee Ka Wai,
Buckton Laura K.,
McAlpine Shelli R.
Publication year - 2016
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201500572
Subject(s) - moiety , chemistry , peptide , biological activity , stereochemistry , cytotoxicity , small molecule , molecule , structure–activity relationship , heat shock protein , hsp90 , combinatorial chemistry , biochemistry , in vitro , organic chemistry , gene
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.