Potent and Highly Selective Inhibitors of the Proteasome Trypsin-like Site by Incorporation of Basic Side Chain Containing Amino Acid Derived Sulfonyl Fluorides

A unique
category of basic side chain containing amino acid derived
sulfonyl fluorides (SFs) has been synthesized for incorporation into
new proteasome inhibitors targeting the trypsin-like site of the 20S
proteasome. Masking the former α-amino functionality of the
amino acid starting derivatives as an azido functionality allowed
an elegant conversion to the corresponding amino acid derived sulfonyl
fluorides. The inclusion of different SFs at the P1 site
of a proteasome inhibitor resulted in 14 different peptidosulfonyl
fluorides (PSFs) having a high potency and an excellent selectivity
for the proteolytic activity of the β2 subunit over that of
the β5 subunit. The results of this study strongly indicate
that a free N-terminus of PSFs inhibitors is crucial for high selectivity
toward the trypsin-like site of the 20S proteasome. Nevertheless,
all compounds are slightly more selective for inhibition of the constitutive
over the immunoproteasome.