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Asymmetric Synthesis of Lysine Analogues with Reduced Basicity, and their Incorporation into Proteasome Inhibitors
Author(s) -
de Bruin Gerjan,
van Rooden Eva J.,
Ward David,
Wesseling Charlotte,
van den Nieuwendijk Adrianus M. C. H.,
van Boeckel Constant A. A.,
Driessen Christoph,
Kisselev Alexei F.,
Florea Bogdan I.,
van der Stelt Mario,
Overkleeft Herman S.
Publication year - 2017
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.201701174
Subject(s) - chemistry , oligopeptide , moiety , lysine , proteasome , amino acid , enantioselective synthesis , stereochemistry , histidine , peptidomimetic , glycine , peptide , biochemistry , catalysis
Most known β2‐selective proteasome inhibitors suffer from relatively poor cell permeability as the result of a net positive charge caused by the basic moiety at P1. In this paper, we describe the synthesis of oligopeptide vinyl sulfones that contain different amino acids bearing amino groups with reduced basicity at P1 and/or P3. For this, we developed the first enantioselective synthesis of lysine(4‐ene) and lysine(4‐yne). These amino acids, as well as histidine and diaminopropionic‐acid‐glycine, were incorporated at the P1 and/or P3 positions of oligopeptide vinyl sulfones. All inhibitors were found to inhibit β2, but with a loss of potency compared to our most potent and selective β2 inhibitor, LU‐102. These results notwithstanding, our results provide important insights for the future design of β2‐selective proteasome inhibitors.