Synthesis of Thiazoline Based Inhibitors for O-GlcNAcase

O-GlcNAcylation is a dynamic post-translational modification that regulates numerous cellular processes and is implicated in several diseases.1-13 This modification is reversed by O- GlcNAcase (OGA) a glycoside hydrolase from the family GH84. Due to the involvement of OGA in disease and the limited understanding of O-GlcNAcylation further understanding of the roles OGA plays are required. To facilitate greater understanding of OGA activity-based probes could play an important role as they selectively label active populations of the target enzyme. For the development of ABPs to start a covalent inhibitor must be found. Covalent binding between the inhibitor and the enzyme is a prerequisite for permanent labelling. Several OGA inhibitors exist, but none are capable of forming a covalent bond to the target enzyme. This thesis addresses the development of novel thiazoline-based OGA inhibitors that contain electrophilic warheads targeted against the catalytic base in OGA and a pocket bound cysteine residue. The research builds upon existing scaffolds such as Thiamet-G, aiming to explore structural analogues that exploit the catalytic mechanism of OGA and its active site configuration. Here, the synthesis and where relevant the biological evaluation of three distinct series of thiazoline-based inhibitors are shown. In Chapter I, efforts to synthesise covalent inhibitors based on epoxide-bearing glucose analogues were met with challenges in regioselectivity and synthetic accessibility. Chapter II details the design and synthesis of thiazoline derivatives bearing electrophilic warheads. These compounds demonstrated micromolar potency in vitro. In Chapter III, further analogues were synthesised containing chloro-, iodo- and bromo- acetic derived analogues of Thiamet-G which showed low nanomolar potency against OGA in vitro.

1. Emilyn U. Alejandro, et al., Cell Reports, 2015, 13, 2527-2538.
2. K. T. Jacobsen and K. Iverfeldt, Biochemical and Biophysical Research
Communications, 2011, 404, 882-886.
3. Y. S. Chun, Y. Park, H. G. Oh, T.-W. Kim, H. O. Yang, M. K. Park and S. Chung,
Journal of Alzheimer's Disease, 2015, 44, 261-275.
4. C. Kim, et al., Neurobiology of Aging, 2013, 34, 275-285.
5. S. A. Yuzwa, et al., Nature Chemical Biology, 2008, 4, 483-490.
6. P. Raman, I. Krukovets, T. E. Marinic, P. Bornstein and O. I. Stenina, Journal of
Biological Chemistry, 2007, 282, 5704-5714.
7. I. G. Lunde, et al., Physiological Genomics, 2012, 44, 162-172.
8. M. V. Cannon, et al., EMBO Molecular Medicine, 2015, 7, 1229-1243.
9. J. S. G. Miguez, et al., Life Sciences, 2018, 209, 78-84.
10. Christina M. Ferrer, et al., Molecular Cell, 2014, 54, 820-831.
11. Y. Liu, et al., EMBO reports, 2023, 24, e56458.
12. Y. Liu, et al., Cell Death & Disease, 2018, 9, 485.
13. C. Wu, J. Li, L. Lu, M. Li, Y. Yuan and J. Li, Journal of Biological Chemistry, 2024,
300.