Bioorganic & Medicinal Chemistry 26 (2018) 2992–2995 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry journal homepage: www.elsevier.com/locate/bmc Thioamide substitution to probe the hydroxyproline recognition of VHL ligands Pedro Soares, Xavier Lucas, Alessio Ciulli Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, UK ar ti c l e i nf o ab stra ct Article history: Thioamide substitution inﬂuences hydrogen bond and n? p interactions involved in the conformational Received 15 February 2018 stability of protein secondary structures and oligopeptides. Hydroxyproline is the key recognition ele- Revised 21 March 2018 ment of small molecules targeting the von Hippel-Lindau (VHL) E3 ligase, which are of interest as probes Accepted 22 March 2018 of hypoxia signaling and ligands for PROTAC conjugation. We hypothesized that VHL ligands could be a Available online 23 March 2018 privileged model system to evaluate the contribution of these interactions to protein:ligand complex for- mation. Herein we report the synthesis of VHL ligands bearing thioamide substitutions at the central Keywords: hydroxyproline moiety, and characterize their binding by ﬂuorescence polarization, isothermal titration Protein-ligand interactions calorimetry, X-ray crystallography and molecular modeling. In spite of a conserved
Bioorganic & Medicinal Chemistry – Elsevier
Published: Jul 15, 2018
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