Design and Synthesis of Arylnaphthalene Lignan Lactone Derivatives as Potent Topoisomerase Inhibitors

Author(s): Wang Chen, Zili Feng*, Daihua Hu, Jin Meng

Journal Name: Medicinal Chemistry

Volume 17 , Issue 8 , 2021

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Graphical Abstract:


Background: Arylnaphthalene lignan lactones are a class of natural products containing the phenyl-naphthyl skeleton. Some arylnaphthalene lignan lactones have been used in clinical practice as antitumor agents, due to their cytotoxicity and inhibitory activities against DNA topoisomerase I (Topo I) and topoisomerase II (Topo II).

Objective: This study presents the design and synthesis of arylnaphthalene lignan lactones derivatives. The inhibitory activities against Topo I and Topo IIα and antitumor activities of these compounds were assayed.

Methods: A series of arylnaphthalene lignan lactones derivatives have been designed and synthesized, using the Diels-Alder reaction and Suzuki reaction as the key steps. Their antiproliferation activities were evaluated by sulforhodamine B assay on human breast cancer MDAMB-231, MDA-MB-435 and human cervical cancer HeLa cells. DNA relaxation assays were employed to examine the inhibitory activity of compounds 1-22 on Topo I and Topo IIα in vitro. Flow cytometry analysis was performed to study the drug effects on cell cycle progressions.

Results: Seven compounds exhibited the modest anti-proliferation activity with IC50 values between 1.36 and 20 μM. Compounds 3, 19 and 22 showed potent inhibitory activities with IC50 values less than 1 μM. DNA relaxation assay revealed that compound 22 showed potent inhibitory activity against Topo IIα in vitro. Compound 22 also induced DNA breaks in MDA-MB-435 cells evidenced by comet tails and the accumulation of γ-H2AX foci. The ability of 22 in inducing DNA breaks mediated by Topo IIα resulted in G2/M phase arrest and apoptosis.

Conclusion: This work indicates that arylnaphthalene lignan lactones derivatives represent a novel type of Topo IIα inhibitory scaffold for developing new antitumor chemotherapeutic agents.

Keywords: Arylnaphthalene lignin lactones, anti-proliferation activity, chemotherapeutic agents, cell proliferation assay, catalytic inhibitor, topoisomerase IIα.

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Article Details

Year: 2021
Published on: 10 June, 2020
Page: [856 - 865]
Pages: 10
DOI: 10.2174/1573406416666200610190417
Price: $65

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