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.

背景：芳萘木脂素内酯是一类含有苯基-萘基骨架的天然产物。一些芳基萘木脂素内酯已在临床实践中用作抗肿瘤剂，因为它们具有细胞毒性和对 DNA 拓扑异构酶 I (Topo I) 和拓扑异构酶 II (Topo II) 的抑制活性。

目的：本研究介绍了芳基萘木脂素内酯衍生物的设计和合成。测定了这些化合物对Topo I和Topo IIα的抑制活性和抗肿瘤活性。

方法：以Diels-Alder反应和Suzuki反应为关键步骤，设计合成了一系列芳基萘木脂素内酯衍生物。通过硫罗丹明 B 测定对人乳腺癌 MDAMB-231、MDA-MB-435 和人宫颈癌 HeLa 细胞的抗增殖活性进行评估。使用 DNA 弛豫试验来检测化合物 1-22 在体外对 Topo I 和 Topo IIα 的抑制活性。进行流式细胞术分析以研究药物对细胞周期进程的影响。

结果：七种化合物表现出适度的抗增殖活性，IC ₅₀值介于 1.36 和 20 μM 之间。化合物 3、19 和 22 显示出有效的抑制活性，IC ₅₀值小于 1 μM。DNA 松弛试验表明，化合物 22 在体外对 Topo IIα 显示出有效的抑制活性。化合物 22 还在 MDA-MB-435 细胞中诱导 DNA 断裂，这由彗尾和 γ-H2AX 病灶的积累证明。22 诱导由 Topo IIα 介导的 DNA 断裂的能力导致 G2/M 期停滞和细胞凋亡。

结论：这项工作表明芳基萘木脂素内酯衍生物代表了一种新型的 Topo IIα 抑制支架，可用于开发新的抗肿瘤化疗药物。