Human DNA topoisomerase IIα (TopoIIα), an Achilles’ heel of cancer, is a well-validated target for antitumor drugs. The inhibitors of TopoIIα are among the most effective and commonly used antitumor drugs in clinic, e. g. etoposide and doxorubicin. However, clinically used v inhibitors exhibited serious side effects including cardiotoxicity, development of secondary malignancies and multidrug resistance, thus that it is urgent to explore novel DNA topoisomerase IIα inhibitors for the development of antitumor drugs.
In the recent work of Shen laboratory, a group of 2-phenylnaphthalenoids (2PNs) and 2-phenylbenzofuranoids (2PBFs) were designed and synthesized for the sake of innovation of DNA topoisomerase IIα inhibitors. These 2PNs and 2PBFs were proved to display favorable TopoIIα inhibitory as well as antiproliferative activities. In particular, 2PBFs possess divergent mechanism of action on inhibiting DNA topoisomerase IIα from 2PNs, switching Topo poisons 2PNs to Topo catalytic inhibitors 2PBFs. These results suggest that the chromophore scaffold replacement drug design strategy used in this study may result in a change of the binding sites of inhibitors to TopoIIα. This study provides insights to the structure optimization of DNA topoisomerase IIα inhibitors.
Eur J Med Chem. 2015;102:277-87.
Hao H1, Chen W1, Zhu J2, Lu C1, Shen Y3.[expand title=”Show Affiliations”]
- Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong, 250012, PR China.
- State Key Laboratory of Microbial Technology, School of Life Sciences, Shandong University, Jinan, Shandong, 250100, PR China.
- Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong, 250012, PR China; State Key Laboratory of Microbial Technology, School of Life Sciences, Shandong University, Jinan, Shandong, 250100, PR China. Electronic address: [email protected] [/expand]
Eight 2-phenylnaphthalenoids (2PNs) (3a-h) and twenty four 2-phenylbenzofuranoids (2PBFs) (4a–4j, 5a-5j, 6a, 6f-6h) were successfully designed, synthesized and their antiproliferative and in vitro DNA topoisomerase inhibitory activities were evaluated. Nine compounds (four 2PNs and five 2PBFs) showed either TopoI or TopoIIα inhibitory activities. Six compounds (four 2PNs and two 2PBFs) exhibited potent cytotoxicity with IC50 values for 72 h exposure ranging from 0.3 to above 20 μM against MDA-MB-231, MDA-MB-435, HepG2 and PC3 cell lines. The two 2PBFs displayed comparable and even better antiproliferative as well as TopoIIα inhibitory activities than 2PNs. Interestingly, the active 2PBFs displayed different mechanisms of TopoIIα inhibition from that of 2PNs, suggesting that the chromophore scaffold replacement may result in a change of the binding site of inhibitors to TopoIIα. Furthermore, the mechanisms of antiproliferation on MDA-MB-231 cells indicate that compounds 5a and 5f are promising for further development of anticancer agents. The results of this study reveal that the evolutionary strategy of medicinal chemistry through scaffold hopping is a promising strategy for structure optimization of TopoIIα inhibitors.
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