Synthesis of purin-2-yl and purin-6-yl-aminoglucitols as C-nucleosidic ATP mimics and biological evaluation as FGFR3 inhibitors

Two new series of C-nucleosidic ATP mimics have been synthesized using an efficient and versatile synthetic pathway. These compounds were designed as FGFR3 inhibitors using purine as a central scaffold. The two substituents, a polyhydroxylated ribose mimic and a lipophilic moiety, were linked either in position 2 or 6 of the purine ring in order to explore any possible binding mode. All the compounds were able to inhibit FGFR3 kinase activity at a concentration of 50 μM. Unexpectedly, the best inhibitor was found to be one of the synthetic intermediates 13 bearing an iodine atom in position 2. Docking studies have confirmed its location in the ATP binding site and revealed halogen bonding among key interactions.

Two new series of C-nucleosidic ATP mimics have been synthesized using an efficient and versatile synthetic pathway. These compounds were evaluated as FGFR3 inhibitors.Figure optionsDownload as PowerPoint slideResearch highlights
► Series of C-nucleosides can be obtained from 2,6-dihalopurine via two SNAr reactions.
► SNAr in position 2 was achieved thanks to NaBF4 catalysis and microwave activation.
► Both series of compounds were able to inhibit FGFR3 kinase activity at 50 μM.
► The most potent inhibitor is a synthetic intermediates derived from 2-iodopurine.
► This iodine atom was found to be involved in halogen bonding by docking studies.