Background: Coumarins possess a broad spectrum of biological activities and are important pharmacophores
in drug developments. Since aberrant upregulation of PI3K/Akt signaling is related to uncontrolled tumor cell
proliferation, enhanced migration, and adhesion-independent tumor growth, it is of interests to find novel coumarin
derivatives as anticancer agents targeting the PI3K/Akt signaling pathway.
Objective: A variety of coumarin derivatives possessing the pyridinylurea units were designed to increase their potency
and isoform selectivity against PI3Ks.
Method: Novel coumarin analogs 4a–m were were prepared from 5-methylpyridin-2-ylamine in a straightforward
way and their growth inhibitory activity against tumor cells was evaluated by a MTT assay. The inhibitory activity
against PI3Kα, β, δ and γ was measured by luminescent assay. Akt phosphorylation inhibition and caspase 3 and PARP
activation were measured by Western blot analysis. Apoptosis was measured by staining cells with annexin V-FITC and
Results: In general, these coumarin analogs exhibited good in vitro growth inhibitory activities against tumor K562,
Hela, A549 and MCF-7 cells. Some of them showed comparable or better potency than BENC-511. Compounds 4b
and 4h were much more potent PI3K inhibitors than S14161 or BENC-511. In addition, 4b was more selective to
PI3Kα/β over PI3Kδ/γ, while 4h was a selective PI3Kα/β/δ inhibitor. Moreover, 4h could suppress the phosphorylation
of Akt and induce K562 cell apoptosis.
Conclusion: Coumarin derivatives possessing the pyridinylurea units are potential PI3K inhibitors and anticancer
agents. These findings will be helpful for the future design of more potent and selective PI3K inhibitors.