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Rational Design and Asymmetric Synthesis of Potent and Neurotrophic Ligands for FK506‐Binding Proteins (FKBPs)
Author(s) -
Pomplun Sebastian,
Wang Yansong,
Kirschner Alexander,
Kozany Christian,
Bracher Andreas,
Hausch Felix
Publication year - 2015
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201408776
Subject(s) - moiety , fkbp , chemistry , amide , rational design , combinatorial chemistry , potency , stereochemistry , biochemistry , in vitro , biology , genetics
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.