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Article

Terephthalamide Derivatives as Mimetics of Helical Peptides: Disruption of the Bcl-x_L/Bak Interaction

Supporting Info

Hang Yin,^† Gui-in Lee,^† Kristine A. Sedey,^‡ Johanna M. Rodriguez,^† Hong-Gang Wang,^‡ Said M. Sebti,^‡ and Andrew D. Hamilton*^†

Contribution from the Department of Chemistry, Yale University, P.O. Box 208107, New Haven, Connecticut 06520-8107, and Drug Discovery Program, H. Lee Moffitt Cancer Center and Research Institute, Departments of Oncology and Biochemistry and Molecular Biology, University of South Florida, Tampa, Florida 33612

J. Am. Chem. Soc., 2005, 127 (15), pp 5463–5468

DOI: 10.1021/ja0446404

Publication Date (Web): March 25, 2005

†

Yale University.

‡

University of South Florida.

In papers with more than one author, the asterisk indicates the name of the author to whom inquiries about the paper should be addressed.

andrew.hamilton@yale.edu

Abstract

A series of Bcl-x_L/Bak antagonists, based on a terephthalamide scaffold, was designed to mimic the α-helical region of the Bak peptide. These molecules showed favorable in vitro activities in disrupting the Bcl-x_L/Bak BH3 domain complex (terephthalamides 9 and 26, K_i = 0.78 ± 0.07 and 1.85 ± 0.32 μM, respectively). Extensive structure−affinity studies demonstrated a correlation between the ability of terephthalamide derivatives to disrupt Bcl-x_L/Bak complex formation and the size of variable side chains on these molecules. Treatment of human HEK293 cells with the terephthalamide derivative 26 resulted in disruption of the Bcl-x_L/Bax interaction in whole cells with an IC₅₀ of 35.0 μM. Computational docking simulations and NMR experiments suggested that the binding cleft for the BH3 domain of the Bak peptide on the surface of Bcl-x_L is the target area for these synthetic inhibitors.