Background::Cycle-regulating and transcriptional cyclin-dependent kinases (CDKs) are
attractive targets in cancer drug development. Several CDK inhibitors have already been obtained or
are close to regulatory approval for clinical applications.
Objective::Phenylazopyrazole CAN508 has been described as the first selective CDK9 inhibitor with
an IC50 of 350 nM. Since the azo-moiety is not a suitable functionality for drugs due to pharmacological
reasons, the preparation of carbo-analogues of CAN508 with similar biological activities is desirable.
The present work is focused on the synthesis of carbo-analogues similar to CAN508 and their
CDK inhibition activity.
Methods::Herein, the synthesis of 21 novel carbo analogues of CAN508 and their intermediates is
reported. Subsequently, target compounds 8a - 8u were evaluated for protein kinase inhibition
(CDK2/cyclin E, CDK4/cyclin D, CDK9/cyclin T) and antiproliferative activities in cell lines (K562,
MCF-7, MV4-11). Moreover, the binding mode of derivative 8s in the active site of CDK9
was modelled.
Results::Compounds 8a - 8u were obtained from key intermediate 7, which was prepared by linear
synthesis involving Vilsmeier-Haack, Knoevenagel, Hunsdiecker, and Suzuki-Miyaura reactions.
Styrylpyrazoles 8t and 8u were the most potent CDK9 inhibitors with IC50 values of approximately 1
μM. Molecular modelling suggested binding in the active site of CDK9. The flow cytometric analysis
of MV4-11 cells treated with the most active styrylpyrazoles showed a significant G1-arrest.
Conclusion::The prepared styrylpyrazoles showed inhibition activity towards CDKs and can provide
a novel chemotype of kinase inhibitors.
