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  • Title: Design and Synthesis of Arylnaphthalene Lignan Lactone Derivatives as Potent Topoisomerase Inhibitors.
    Author: Chen W, Feng Z, Hu D, Meng J.
    Journal: Med Chem; 2021; 17(8):856-865. PubMed ID: 32520691.
    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.
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