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

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

Volume: 17 Issue: 8

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

Affiliation:

• College of Biological Science & Engineering, Shaanxi University of Technology, Hanzhong,China

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

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.

Cite this article as:

Chen Wang , Feng Zili *, Hu Daihua and Meng Jin , Design and Synthesis of Arylnaphthalene Lignan Lactone Derivatives as Potent Topoisomerase Inhibitors, Medicinal Chemistry 2021; 17 (8) . https://dx.doi.org/10.2174/1573406416666200610190417