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Title: Basic side chain containing amino acid derived peptido sulfonyl fluorides : an approach to future β2 selective proteasome inhibitors
Author: Artschwager, Raik
ISNI:       0000 0004 6421 7866
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 2017
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Peptido sulfonyl fluorides are a relatively new class of protease inhibitors which have undergone considerable development in recent years. Due to the right balance of reactivity and chemical stability, the sulfonyl fluoride moiety is denoted as a “privileged warhead” in chemical biology nowadays. This thesis describes the development of basic side chain containing amino acid derived sulfonyl fluorides and their incorporation into peptide inhibitor sequences which were unavailable until this point. The resulting peptido sulfonyl fluoride inhibitors (PSFs) are designed to target proteases which require a basic side chain at the P1 position. The synthesis of the sulfonyl fluoride derived from arginine was accomplished applying the standard synthetic route for the introduction of the sulfonyl fluoride warhead previously developed in the LISKAMP group. A slight modification of this synthetic route by masking the former N-terminus with an azido functionality led to the successful synthesis of lysine, 4-amino- and 4-aminomethyl phenylalanine derived sulfonyl fluorides. The challenging incorporation of the sulfonyl fluoride warhead molecules into peptide inhibitor sequences resulted in a library of 14 different PSF inhibitors to target the 20S proteasome trypsin-like site. Structure-activity relationship studies showed that the synthesised PSFs were highly potent (IC50 values ranges from 119 nM - 1.5 µM) and highly selective for the proteasome trypsin-like site (up to ~1000-fold). Furthermore, the results indicated that a free N-terminus in a PSF inhibitor is crucial for selectivity towards the trypsin-like site over the chymotrypsin-like site. Additionally, as an attempt to overcome the limitation of installing the SF moiety only at the C-terminus in an amino acid, cysteine derivatives ontaining the sulfonyl fluoride moiety in the side chain were synthesised, allowing the incorporation of these molecules at any desired position of a peptide sequence. Finally, to further explore the potential of the sulfonyl fluorides and as a proof of concept, a potentially fluorescent probe exhibiting the sulfonyl fluoride was synthesised.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QD Chemistry