Rational Design and Asymmetric Synthesis of Potent and Neurotrophic Ligands for 
FK506-Binding Proteins (FKBPs)

Pomplun, Sebastian; Wang, Yansong; Kirschner, Alexander; Kozany, Christian; Bracher, Andreas; Hausch, Felix

doi:10.1002/anie.201408776

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Rational Design and Asymmetric Synthesis of Potent and Neurotrophic Ligands for FK506-Binding Proteins (FKBPs)

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Bracher, Andreas
Hartl, Franz-Ulrich / Cellular Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society;

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Citation

Pomplun, S., Wang, Y., Kirschner, A., Kozany, C., Bracher, A., & Hausch, F. (2015). Rational Design and Asymmetric Synthesis of Potent and Neurotrophic Ligands for FK506-Binding Proteins (FKBPs). ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 54(1), 345-348. doi:10.1002/anie.201408776.

Cite as: https://hdl.handle.net/11858/00-001M-0000-0024-AA70-3

Abstract

To create highly efficient inhibitors for FK506-binding proteins, a new asymmetric synthesis for pro-(S)-C-5-branched [4.3.1] aza-amide bicycles was developed. The key step of the synthesis is an HF-driven N-acyliminium cyclization. Functionalization of the C(5)moiety resulted in novel protein contacts with the psychiatric risk factor FKBP51, which led to a more than 280-fold enhancement in affinity. The most potent ligands facilitated the differentiation of N2a neuroblastoma cells with low nanomolar potency.