Purine nucleoside library

The nucleoside scaffold has traditionally been considered a privileged scaffold for the discovery of antiviral and antitumor agents. This has resulted in the FDA-approval or clinical use of 43 nucleoside analogues. Therefore, it can be stated that the evaluation of nucleoside libraries remains a potential source to identify interesting starting points for further development in these indications. Particularly, the evaluation of new or underexplored modifications to the nucleoside scaffold is of interest.

Extensive literature evaluation (published journal articles and patent literature) uncovered significant ‘gaps’ in prepared nucleoside analogues (e.g. several sugar-ring modifications have only been explored with a pyrimidine nucleobase; the sugar ring of some purine nucleoside analogues was never thoroughly investigated). Additionally, the evaluation of libraries containing purine C-nucleosides, analogues that feature a carbon atom as the connecting element to the sugar, as opposed to the canonical nitrogen, has been seldom performed. Thus, in the LMC we have taken a ligand-based approach to construct a purine nucleoside library, based on the primary structure of the nucleoside (‘sugar ring’ and ‘nucleobase’) as the design principle.

In this regard, several sugar ring and heterocycle scaffolds were separately selected, then recombined and the corresponding nucleoside synthesized to create library members. The inclusion of scaffolds was inspired by their presence in the structure of FDA-approved nucleoside drugs, advanced clinical candidates or from other known bioactive scaffolds. This latter group was mainly inspired by so-called nucleoside antibiotics such as tubercidin (7-deazaadenosine) and cordycepin (3’-deoxyadenosine). An overview of the current nucleoside library is depicted in Figure 1.


Figure 1: Overview of nucleoside modifications present in the LMC purine library.

Currently, our library consists of over 600 novel and structurally diverse purine nucleoside analogues. Additionally, the LMC has access to significant amounts of advanced intermediates for the swift generation of follow-up analogues to enable hit expansion/lead optimization efforts.

As a proof-of-principle for the potential usefulness of this purine nucleoside library, these analogues have been extensively profiled for activity against pathogenic protozoa, such as the kinetoplastid parasites Trypanosoma brucei spp., Trypanosoma cruzi and Leishmania spp. This screening has resulted in a significant hit rate of ~5-8% confirmed hits, of which several series were subsequently optimized to yield lead analogues showing promising activity in relevant animal models after oral dosing.1-4



  1. Hulpia, F.;  Van Hecke, K.;  Franca da Silva, C.;  da Gama Jaen Batista, D.;  Maes, L.;  Caljon, G.;  de Nazare, C. S. M.; Van Calenbergh, S., Discovery of novel 7-aryl 7-deazapurine 3'-deoxy-ribofuranosyl nucleosides with potent activity against Trypanosoma cruzi. J. Med. Chem. 2018, 61 (20), 9287-9300.
  2. Hulpia, F.;  Campagnaro, G. D.;  Scortichini, M.;  Van Hecke, K.;  Maes, L.;  de Koning, H. P.;  Caljon, G.; Van Calenbergh, S., Revisiting tubercidin against kinetoplastid parasites: aromatic substitutions at position 7 improve activity and reduce toxicity. Eur. J. Med. Chem. 2019, 164, 689-705.
  3. Hulpia, F.;  Mabille, D.;  Campagnaro, G. D.;  Schumann, G.;  Maes, L.;  Roditi, I.;  Hofer, A.;  de Koning, H. P.;  Caljon, G.; Van Calenbergh, S., Combining tubercidin and cordycepin scaffolds results in highly active candidates to treat late-stage sleeping sickness. Nat. Commun. 2019, 10 (1), 5564.
  4. Lin, C.;  Hulpia, F.;  da Silva, C. F.;  Batista, D.;  Van Hecke, K.;  Maes, L.;  Caljon, G.;  Soeiro, M. N. C.; Van Calenbergh, S., Discovery of pyrrolo[2,3-b]pyridine (1,7-dideazapurine) nucleoside analogues as anti-Trypanosoma cruzi agents. J. Med. Chem. 2019, 62 (19), 8847-8865.