- Design and synthesis of arylnaphthalene lignan lactone derivatives as potent topoisomerase inhibitors
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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.
- Chen, Wang,Feng, Zili,Hu, Daihua,Meng, Jin
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p. 856 - 865
(2021/10/21)
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- Directed, DDQ-Promoted Benzylic Oxygenations of Tetrahydronaphthalenes
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Positional preferences for para benzylic oxygenation of tetrahydronaphthalenes by 2,3-dichloro5,6-dicyano-1,4-benzoquinone (DDQ)-aqueous dioxane were investigated by comparing the tetralone products from 6-hydroxy-7-methoxy- and 6-acetoxy-7-methoxy-1,2,3,
- Ramdayal, Frank D.,Kiemle, David J.,LaLonde, Robert T.
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p. 4607 - 4609
(2007/10/03)
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- Novel selective PDE IV inhibitors as antiasthmatic agents. Synthesis and biological activities of a series of 1-aryl-2,3- bis(hydroxymethyl)naphthalene lignans
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A series of 1-aryl-2,3-bis(hydroxymethyl)naphthalene lignans have been synthesized and evaluated for their ability to selectively inhibit PDE IV isolated from guinea pig. Replacement of the 1-phenyl ring by a pyridone ring led to marked improvement of the
- Iwasaki, Tameo,Kondo, Kazuhiko,Kuroda, Tooru,Moritani, Yasunori,Yamagata, Shinsuke,Sugiura, Masaki,Kikkawa, Hideo,Kaminuma, Osamu,Ikezawa, Katsuo
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p. 2696 - 2704
(2007/10/03)
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