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.
CONCLUSIONS: This work indicates that arylnaphthalene lignan lactones derivatives represent a novel type of Topo IIα inhibitory scaffold for developing new antitumor chemotherapeutic agents.
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.
CONCLUSIONS: This work indicates that arylnaphthalene lignan lactones derivatives represent a novel type of Topo IIα inhibitory scaffold for developing new antitumor chemotherapeutic agents.
摘要：
背景:芳基萘木脂素内酯是一类含有苯基-萘基骨架的天然产物。一些芳基萘木酚素内酯已在临床实践中用作抗肿瘤药，由于它们对DNA拓扑异构酶I（TopoI）和拓扑异构酶II（TopoII）的细胞毒性和抑制活性。
目的：本研究介绍了芳基萘木酚素内酯衍生物的设计和合成。测定了这些化合物对TopoI和TopoIIα的抑制活性和抗肿瘤活性。
方法：设计并合成了一系列芳基萘木酚内酯衍生物，以Diels-Alder反应和Suzuki反应为关键步骤。通过对人乳腺癌MDAMB-231，MDA-MB-435和人宫颈癌HeLa细胞的磺基罗丹明B测定法评估了它们的抗增殖活性。采用DNA弛豫测定法来检测化合物1-22对TopoI和TopoIIα的体外抑制活性。进行流式细胞术分析以研究药物对细胞周期进展的影响。
结果:7种化合物表现出适度的抗增殖活性,IC50值在1.36和20μM之间。化合物3、19和22显示出有效的抑制活性,IC50值小于1μM。DNA弛豫分析显示,化合物22在体外对TopoIIα显示出有效的抑制活性。化合物22还诱导MDA-MB-435细胞中的DNA断裂,这由彗星尾和γ-H2AX灶的积累证明。22诱导TopoIIα介导的DNA断裂的能力导致G2/M期停滞和凋亡。
结论：这项工作表明，芳基萘木酚素内酯衍生物代表了一种新型的TopoIIα抑制支架，用于开发新的抗肿瘤化学治疗剂。
目的：本研究介绍了芳基萘木酚素内酯衍生物的设计和合成。测定了这些化合物对TopoI和TopoIIα的抑制活性和抗肿瘤活性。
方法：设计并合成了一系列芳基萘木酚内酯衍生物，以Diels-Alder反应和Suzuki反应为关键步骤。通过对人乳腺癌MDAMB-231，MDA-MB-435和人宫颈癌HeLa细胞的磺基罗丹明B测定法评估了它们的抗增殖活性。采用DNA弛豫测定法来检测化合物1-22对TopoI和TopoIIα的体外抑制活性。进行流式细胞术分析以研究药物对细胞周期进展的影响。
结果:7种化合物表现出适度的抗增殖活性,IC50值在1.36和20μM之间。化合物3、19和22显示出有效的抑制活性,IC50值小于1μM。DNA弛豫分析显示,化合物22在体外对TopoIIα显示出有效的抑制活性。化合物22还诱导MDA-MB-435细胞中的DNA断裂,这由彗星尾和γ-H2AX灶的积累证明。22诱导TopoIIα介导的DNA断裂的能力导致G2/M期停滞和凋亡。
结论：这项工作表明，芳基萘木酚素内酯衍生物代表了一种新型的TopoIIα抑制支架，用于开发新的抗肿瘤化学治疗剂。
