Chemical synthesis of 4′-thio and 4′-sulfinyl pyrimidine nucleoside analogues

Guinan, Mieke; Huang, Ningwu; Hawes, Chris S.; Lima, Marcelo A.; Smith, Mark; Miller, Gavin J.

Abstract

Analogues of the canonical nucleosides required for nucleic acid synthesis have a longstanding presence and proven capability within antiviral and anticancer research. 4'-Thionucleosides, that incorporate bioisosteric replacement of furanose oxygen with sulfur, represent an important chemotype within this field. Established herein is synthetic capability towards a common 4-thioribose building block that enables access to thio-ribo and thio-arabino pyrimidine nucleosides, alongside their 4'-sulfinyl derivatives. In addition, this building block methodology is templated to deliver 4'-thio and 4'-sulfinyl analogues of the established anticancer drug gemcitabine. Cytotoxic capability of these new analogues is evaluated against human pancreatic cancer and human primary glioblastoma cell lines, with observed activities ranging from low μM to >200 μM; explanation for this reduced activity, compared to established nucleoside analogues, is yet unclear. Access to these chemotypes, with thiohemiaminal linkages, will enable a wider exploration of purine and triphosphate analogues and the application of such materials for potential resistance towards relevant hydrolytic enzymes within nucleic acid biochemistries.

Citation

Guinan, M., Huang, N., Hawes, C. S., Lima, M. A., Smith, M., & Miller, G. J. (2021). Chemical synthesis of 4′-thio and 4′-sulfinyl pyrimidine nucleoside analogues. Organic and Biomolecular Chemistry, 20(7), 1401-1406. https://doi.org/10.1039/d1ob02097h

• Journal Article Type: Article
• Acceptance Date: Nov 11, 2021
• Online Publication Date: Nov 11, 2021
• Publication Date: Nov 22, 2021
• Publicly Available Date: May 30, 2023
• Journal: Organic & Biomolecular Chemistry
• Print ISSN: 1477-0520
• Electronic ISSN: 1477-0539
• Publisher: Royal Society of Chemistry
• Peer Reviewed: Peer Reviewed
• Volume: 20
• Issue: 7
• Pages: 1401-1406
• DOI: https://doi.org/10.1039/d1ob02097h
• Public URL: https://keele-repository.worktribe.com/output/421886
• Publisher URL: https://pubs.rsc.org/en/content/articlelanding/2022/OB/D1OB02097H