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
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.