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

Author(s):

Wang Chen, Zili Feng*, Daihua Hu and Jin Meng   Pages 1 - 10 ( 10 )

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 as antitumor agents, due to their cytotoxicity and inhibitory activities against DNA topoisomerase I (Topo I) and topoisomerase II (Topo II).

Objective: We present 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.

Method: A series of arylnaphthalene lignan lactones derivatives have been designed and synthesized, using 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 progression.

Results: Seven compounds exhibited 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 lignan lactones, topoisomerase IIα, catalytic inhibitor, anti-proliferation activity

Affiliation:

College of Biological Science & Engineering, Shaanxi University of Technology, Hanzhong, College of Biological Science & Engineering, Shaanxi University of Technology, Hanzhong, College of Biological Science & Engineering, Shaanxi University of Technology, Hanzhong, Department of Pharmacy, Luohe Medical College, Luohe



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