Synthesis and Investigation of S-Substituted 2-Mercaptobenzoimidazoles as Inhibitors of Hedgehog Signaling

Simone Gräßle; Steven Susanto; Sonja Sievers; Emel Tavsan; Martin Nieger; Nicole Jung; Stefan Bräse

doi:10.1021/acsmedchemlett.7b00100

Synthesis and Investigation of S-Substituted 2-Mercaptobenzoimidazoles as Inhibitors of Hedgehog Signaling

ACS Med Chem Lett. 2017 Jul 28;8(9):931-935. doi: 10.1021/acsmedchemlett.7b00100. eCollection 2017 Sep 14.

Authors

Simone Gräßle¹, Steven Susanto¹, Sonja Sievers², Emel Tavsan¹, Martin Nieger³, Nicole Jung^{1

4}, Stefan Bräse^{1

4}

Affiliations

¹ Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Campus North, Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany.
² Max Planck Institute of Molecular Physiology, Otto-Hahn-Str. 11, 44227 Dortmund, Germany.
³ Department of Chemistry, University of Helsinki, P.O. Box 55, FI-00014 Helsinki, Finland.
⁴ Institute of Organic Chemistry, Karlsruhe Institute of Technology, Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany.

Abstract

Due to the arising resistance of common drugs targeting the Hedgehog signaling pathway, the identification of new compound classes with inhibitory effect is urgently needed. We were able to identify S-alkylated 2-mercaptobenzoimidazoles as a new compound class that exhibits Hedgehog signaling activity in a low micromolar range. The scope of the 2-mercaptobenzoimidazole motif has been investigated by the syntheses of diverse derivatives, revealing that the elongation of the linker unit and the exchange of particular substitution patterns are tolerable with respect to the activity of the compound class.

Keywords: 2-mercaptobenzoimidazoles; Hedgehog signaling; cancer; small molecules.