Synthesis and biological evaluation of selective and potent cyclin-dependent kinase inhibitors

A new series of 2,6,9-trisubstituted purines, structurally related to the cyclin-dependent kinase (CDK) inhibitor Roscovitine, has been synthesized. These compounds mainly differ by the substituent on the C-2 position which encompasses a diol group. These compounds were screened for kinase inhibitory activities and antiproliferative effects. They were shown to be potent inhibitors of cyclin-dependent kinases but also, for some of them of casein kinase 1 (CK1) and dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A). The inhibition of kinases was accompanied by an antiproliferative effect against several tumor cell-lines. The most potent derivatives inhibited SH-SY5Y (neuroblastoma) tumor cell line with an IC50 < 0.5 μM which means approximately a 30 fold increase compared to Roscovitine. A valine ester was also prepared from the most potent inhibitor to serve as a prodrug.

Purine derivatives were prepared and assayed against various protein kinases. Several of the prepared compounds displayed sub-micromolar inhibitory activity on the proliferation of SHSY-5Y tumor cells.Figure optionsDownload as PowerPoint slideHighlights
► Identification of inhibitors of cyclin-dependent kinases, CK1 and DYRK1A.
► A mono ester which could behave as a prodrug was prepared with valine and appeared to be a potent kinase inhibitor.
► The most potent compound showed favorable preliminary ADME properties with no inhibition of CYP 450 enzymes below 5 μM.