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A series of new thiazole-based stilbene analogs were designed, synthesized and evaluated for DNA topoisomerase IB (Top1) inhibitory activity. Top1-mediated relaxation assays showed that the synthesized compounds possessed variable Top1 inhibitory activity. Among them, (<i>E</i>)-2-(3-methylstyryl)-4-(4-fluorophenyl)thiazole (<b>8</b>) acted as a potent Top1 inhibitor with high Top1 inhibition of ++++ which is comparable to that of CPT. A possible binding mode of compound <b>8</b> with Top1–DNA complex was further provided by molecular docking. An MTT assay against human breast cancer (MCF-7) and human colon cancer (HCT116) cell lines revealed that the majority of these compounds showed high cytotoxicity, with IC₅₀ values at micromolar concentrations. Compounds <b>8</b> and (<i>E</i>)-2-(4-tert-butylstyryl)-4-(4-fluorophenyl)thiazole (<b>11</b>) exhibited the most potent cytotoxicity with IC₅₀ values of 0.78 and 0.62 μM against MCF-7 and HCT116, respectively. Moreover, the preliminary structure–activity relationships of thiazole-based stilbene analogs was also discussed.