Synthetic nucleosides, nucleotides and their analogs/mimetics have attracted much attention in organic and in medicinal chemistry, due to their propensity to exhibit a variety of biological properties. Various examples of nucleoside and nucleotide analogs have reached clinical application as anticancer or antiviral drugs, acting through interference with nucleic acid biosynthesis. The ability of these types of molecules to show antimicrobial effects or to inhibit cholinesterases has also been reported. The search for new structures of nucleos(t)ide analogs that may potentiate innovative mechanisms of action and open new therapeutic opportunities remains of interest.

In this context, in this communication we present the synthesis and biological evaluation of novel nucleosides constructed on D-glucuronamide motifs, which are rather uncommon glycosyl units in nucleoside chemistry, and purine isonucleosides. Among the latter groups of compounds, theobromine derivatives were specially focused and related isonucleotide analogs comprising anomeric sulfonamide or phosphoramidate groups were also accessed. The synthetic strategies employed glucofuranurono-6,3-lactone and methyl glucosides as precursors and involved N-glycosylation, Mitsunobu coupling or Staudinger-phosphite reaction as key steps.

D-Glucuronamide-based nucleosides were shown to display significant antiproliferative activities in cancer cells, in some cases comparable or lower than those of a standard drug. Further studies demonstrated the ability of the most active molecules to induce or activate apoptosis. Low micromolar inhibitors of acetylcholinesterase were found among theobromine isonucleos(t)ides, indicating the interest of these types of structural skeletons in the search for new lead compounds for Alzheimer’s disease.

Acknowledgements: Fundação para a Ciência e Tecnologia is acknowledged for funding through projects projects UIDB/00100/2020, UIDP/00100/2020 and grant CEECIND/03881/2018.