Nucleoside analogues have proven to be highly successful chemotherapeutic agents in the treatment of a wide variety of cancers. Several such compounds, including gemcitabine and cytarabine, are the go-to option in first-line treatments. However, these materials do have limitations and the development of next generation compounds remains a topic of significant interest and necessity. Herein, we discuss recent advances in the chemical synthesis and biological evaluation of nucleoside analogues as potential anticancer agents. Focus is paid to 4′-heteroatom substitution of the furanose oxygen, 2′-, 3′-, 4′- and 5′-position ring modifications and the development of new prodrug strategies for these materials.

No abstract

Synthesis of 4-thioribose building blocks and related 4′-thio and 4′-sulfinyl nucleoside analogues.

No abstract

Analogues of the canonical nucleosides required for nucleic acid synthesis have a longstanding presence and proven capability within antiviral and anticancer research. Despite their success, newer generations of such analogues are required, to overcome issues surrounding cellular proficiency and growing resistance profiles. The chemical synthesis of a series of nucleoside analogues that incorporate bioisosteric replacement of furanose oxygen with sulfur is presented herein. Developing access to a common 4-thioribose building block 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 such materials for resistance towards relevant hydrolytic enzymes within nucleotide and nucleic acid biochemistries.