Selective activation of prodrugs in breast cancer using metabolic glycoengineering and the tetrazine ligation bioorthogonal reaction

Mitry, M. M.A., Dallas, M. ORCID: https://orcid.org/0000-0002-5190-0522, Boateng, S. Y., Greco, F. and Osborn, H. M.I. ORCID: https://orcid.org/0000-0002-0683-0457 (2024) Selective activation of prodrugs in breast cancer using metabolic glycoengineering and the tetrazine ligation bioorthogonal reaction. Bioorganic Chemistry, 147. 107304. ISSN 0045-2068 doi: 10.1016/j.bioorg.2024.107304

Abstract/Summary

Increasing the selectivity of chemotherapies by converting them into prodrugs that can be activated at the tumour site decreases their side effects and allows discrimination between cancerous and non-cancerous cells. Herein, the use of metabolic glycoengineering (MGE) to selectively label MCF-7 breast cancer cells with tetrazine (Tz) activators for subsequent activation of prodrugs containing the trans-cyclooctene (TCO) moiety by a bioorthogonal reaction is demonstrated. Three novel Tz-modified monosaccharides, Ac4ManNTz 7, Ac4GalNTz 8, and Ac4SiaTz 16, were used for expression of the Tz activator within sialic-acid rich breast cancer cells’ surface glycans through metabolic glycoengineering. Tz expression on breast cancer cells (MCF-7) was evaluated versus the non-cancerous L929 fibroblasts showing a concentration-dependant effect and excellent selectivity with ≥ 35-fold Tz expression on the MCF-7 cells versus the non-cancerous L929 fibroblasts. Next, a novel TCO-N-mustard prodrug along with a TCO-doxorubicin prodrug were analyzed in vitro on the Tz-bioengineered cells to probe our hypothesis that these could be activated via a bioorthogonal reaction. Selective prodrug activation and restoration of cytotoxicity were demonstrated for the MCF-7 breast cancer cells versus the non-cancerous L929 cells. Restoration of the parent drug’s cytotoxicity was shown to be dependent on the level of Tz expression where the Ac4ManNTz 7 and Ac4GalNTz 8 derivatives (20 µM) lead to the highest Tz expression and full restoration of the parent drug’s cytotoxicity. This work suggests the feasibility of combining MGE and tetrazine ligation for selective prodrug activation in breast cancer.

Item Type	Article
URI	https://reading-clone.eprints-hosting.org/id/eprint/115843
Identification Number/DOI	10.1016/j.bioorg.2024.107304
Refereed	Yes
Divisions	Interdisciplinary centres and themes > Chemical Analysis Facility (CAF) Life Sciences > School of Biological Sciences > Biomedical Sciences Life Sciences > School of Chemistry, Food and Pharmacy > School of Pharmacy > Medicinal Chemistry Research Group Life Sciences > School of Chemistry, Food and Pharmacy > School of Pharmacy > Division of Pharmacology Life Sciences > School of Chemistry, Food and Pharmacy > School of Pharmacy > Pharmaceutics Research Group
Publisher	Elsevier
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