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• Novel perimidine o -quinone derivatives were synthesized as Topo II inhibitors. • Compound b-12 showed potent cytotoxicity (IC 50 < 1 μM) against four cancer cell lines. • Compound b-12 showed strong Topo IIα inhibitory activity (IC 50 = 7.54 μM). • Compound b-12 is a calss of novel non-intercalative Topo IIα catalytic inhibitor. For the development of novel anticancer agents, we designed and synthesized a total of 37 perimidine o -quinone derivatives containing the o -quinone group at the A or B ring and different substituents (alkyl groups, aryl groups or heterocycles) at the C ring of the compounds. The structure-activity relationships (SARs) were established based on the cytotoxicity data of compounds from the HL-60, Huh7, Hct116, and Hela cell lines. The cytotoxicity results showed that most compounds exhibited potent cytotoxicity. In particular, compound b-12 showed the best anti-proliferative activity (IC 50 ≤ 1 μM) against four cancer cell lines and strong potency against the HL-60/MX2 (0.47 μM) cell line, which is resistant to Topo II poisons. Further studies showed that b-12 exhibited potent Topo IIα inhibitory activity (IC 50 = 7.54 μM) compared with Topo I, which acted as a class of non-intercalative Topo IIα catalytic inhibitor by inhibiting the ATP binding site of Topo II. Cell apoptosis and cell cycle assays confirmed that b-12 could induce the apoptosis of Huh7 cells in a dose-dependent manner. [ABSTRACT FROM AUTHOR]