3-Substituted-4-hydroxycoumarin as a new scaffold with potent CDK inhibition and promising anticancer effect: Synthesis, molecular modeling and QSAR studies

• 3-Substituted 4-hydroxycoumarin derivatives were synthesized.
• All the synthesized target compounds selectively inhibited CDK1B.
• 3a, 6b and 8c showed in vitro and in vivo anticancer effects against MCF-7.
• The Docking study confirmed a unique binding mode in CDK1B active site.
• QSAR study revealed high predictive power (R2 = 0.81).

A new series of 3-substituted-4-hydroxycoumarin derivatives was designed, synthesized, and evaluated for CDK inhibiting and anticancer activities. All the synthesized target compounds showed remarkably high affinity and selectivity towards CDK1B, compared to flavopiridol, with Ki values in the low nanomolar range (Ki = 0.35–0.88 nM). Most of them elicited considerable inhibiting effect against CDK9T1 (Ki = 3.26–23.45 nM). Moreover, all the target compounds were tested in vitro against eighteen types of human tumor cell lines. The hydrazone 3a, N-phenylpyrazoline derivative 6b and 2-aminopyridyl-3-carbonitrile derivative 8c were the most potent anticancer agents against MCF-7 breast cancer cell line (IC50 = 0.21, 0.21 and 0.23 nM, respectively). The target compounds 3a, 6b and 8c were further evaluated in MCF-7 breast cancer mouse xenograft model and showed in vivo efficacy at 10 mg/kg dose. The docking study confirmed a unique binding mode in the active site of CDK1B with better score than flavopiridol. Quantitative structure activity relationship study was done and revealed a highly predictive power R2 of 0.81.

3-Substituted-4-hydroxycoumarin as a new scaffold with potent CDK inhibition and promising anticancer effect: synthesis, molecular modeling and QSAR studies.Figure optionsDownload as PowerPoint slide