Design, synthesis and preliminary biological evaluation of C-8 substituted guanine derivatives as small molecular inhibitors of FGFRs

Two series of C-8 substituted guanine derivatives were synthesized, one bearing 2-amino substitutions and the other bearing 2-acetamide substitutions. Biological activity tests showed that almost all of them possessed some extent of antitumor activities, and were with lower toxicity against normal human liver HL7702 cells than AZD4547 (the positive control). Among them, N-[8-(4-bromo-1H-indol-3-yl)-6-hydroxy-9H-purin-2-yl]-acetamide exhibited a relatively satisfied inhibition against FGFR1 kinase with IC50 of 1.56 μM and specifically against A549 cells with IC50 of 8.28 μM and B16-F10 cells with IC50 of 6.59 μM. Above all, the introduction of large substituents such as indolyl groups at 8-position of the guanine scaffold probably achieves higher selectivity for FGFR1 as compared with AZD4547.

Novel C-8 substituted guanine derivatives were synthesized and evaluated for FGFR1-4 inhibition and anti-cancer activities in vitro.Figure optionsDownload as PowerPoint slide