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.

Analogues of the canonical nucleosides have a longstanding presence and proven capability within medicinal chemistry and drug discovery research. The synthesis reported herein successfully replaces furanose oxygen with CF2 and...

Analogues of the canonical nucleosides have a longstanding presence and proven capability within medicinal chemistry and drug discovery research. Herein we report chemical diversification of carbocyclic pyrimidine nucleosides, containing CF2 and CHF in place of furanose oxygen, to introduce ring unsaturation and 2’-epimers. Utilising gram-scale access to 6’-(R)-monofluoro- and 6’-gem-difluorouridine we explore provision of 2’,3’-didehydro-2’,3’-dideoxy and 1’,2’-didehydro-2’-deoxy analogues, alongside the first example of 6’-(R)-fluoroarabino carbauridine. Key stereochemistries and the presence of unsaturation are confirmed using X-ray crystallography and NMR, and an indicative conformational preference for a monofluoro 2’,3’-didehydro-2’,3’-dideoxy system is presented. This synthetic blueprint offers potential to explore biological activity for these hitherto unavailable materials, including for direct comparison to established nucleoside analogue drugs.

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