Design and Synthesis of Coumarin Derivatives as Novel PI3K Inhibitors

Author(s): Chen-Chen Ma, Zhao-Peng Liu

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

Volume 17 , Issue 3 , 2017

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Graphical Abstract:


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 7-AAD.

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.

Keywords: Anticancer agents, apoptosis, coumarins, Friedel-Crafts alkylation, inhibitors, Pechman reaction, PI3K, PI3K/Akt signal pathway.

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Article Details

Year: 2017
Page: [395 - 403]
Pages: 9
DOI: 10.2174/1871520616666160223120207
Price: $65

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