Basic side chain containing amino acid derived Peptido sulfonyl fluorides: an approach to future β2 selective proteasome inhibitors

Artschwager, Raik (2017) Basic side chain containing amino acid derived Peptido sulfonyl fluorides: an approach to future β2 selective proteasome inhibitors. PhD thesis, University of Glasgow.

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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.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: 1. L. Gilfillan, R. Artschwager, A. H. Harkiss, R. M. J. Liskamp and A. Sutherland Org. Biomol. Chem. 2015, 13, 4514–4523. 2. C. O’Connor, F. Lohan, J. Campos, E. Ohlsson, M. Salomè, C. Forde, R. Artschwager, R. M. J. Liskamp, M. R. Cahill, P. A. Kiely, B. Porse and K. Keeshan Oncogene 2016, 35, 5272–5281.
Keywords: Peptido sulfonyl fluorides, basic side chain, amino acids, 20S proteasome inhibitor, trypsin-like, chymotrypsin-like.
Subjects: Q Science > QD Chemistry
Colleges/Schools: College of Science and Engineering > School of Chemistry
Supervisor's Name: Liskamp, Professor Robert M. J.
Date of Award: 2017
Embargo Date: 25 October 2021
Depositing User: Mr Raik Artschwager
Unique ID: glathesis:2017-8534
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 25 Oct 2017 14:50
Last Modified: 27 Oct 2020 09:26
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