Exploring a Gemcitabine-Glucose Hybrid as a Glycoconjugate Prodrug

Porter, Jack; Noble, Amanda R.; Signoret, Nathalie; Fascione, Martin A.; Miller, Gavin J.

Abstract

Nucleoside analogues are established treatments for cancer and viral infection. Gemcitabine is a commonly employed nucleoside analogue displaying anticancer properties against a range of tumor types but is rapidly inactivated in vivo. Efforts to bolster its pharmaceutical profile include investigating prodrug forms. Herein, we explore the synthesis of a novel glucose-gemcitabine glycoconjugate, targeting uptake via glucose transport. We select a redox-reactive disulfide linker for conjugation of gemcitabine (through N4-cytosine) with glucose. Evaluation of this glycoconjugate reveals increased toxicity against androgen insensitive PC3 prostate cancer cells compared to LNCaP (which have lower levels of glucose transporter GLUT1). These preliminary results suggest that glycoconjugation of nucleosides may be an effective approach to targeting cells which display increased uptake and metabolism of glucose.

Citation

Porter, J., Noble, A. R., Signoret, N., Fascione, M. A., & Miller, G. J. (in press). Exploring a Gemcitabine-Glucose Hybrid as a Glycoconjugate Prodrug. ACS Omega, 9(29), 31703-31713. https://doi.org/10.1021/acsomega.4c02417

• Journal Article Type: Article
• Acceptance Date: Jun 21, 2024
• Online Publication Date: Jul 9, 2024
• Deposit Date: Aug 8, 2024
• Journal: ACS Omega
• Electronic ISSN: 2470-1343
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 9
• Issue: 29
• Pages: 31703-31713
• DOI: https://doi.org/10.1021/acsomega.4c02417
• Keywords: Carbohydrates; Column chromatography; Disulfides; Mixtures; Pharmaceuticals
• Public URL: https://keele-repository.worktribe.com/output/878092