Abstract
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, (E)-2-(3-methylstyryl)-4-(4-fluorophenyl)thiazole (8) acted as a potent Top1 inhibitor with high Top1 inhibition of ++++ which is comparable to that of CPT. A possible binding mode of compound 8 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 8 and (E)-2-(4-tert-butylstyryl)-4-(4-fluorophenyl)thiazole (11) 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.
Highlights
Nowadays, cancer is considered to be one of the most common diseases causing death and has been a huge health burden worldwide
According to our experimental results, the sole benzylic brominated product was almost impossible to obtain via a single benzylic bromination step due to the higher reactivity of the proton at the 5-position relative to that at the benzylic position, and the attempt to synthesize intermediates 4 in a one-pot process by using excess NBS only gave a low yield of intermediates 4
Top1-mediated assays revealed that the synthesized compounds could act as Top1 inhibitors, and compound 8 exhibited the highest Top1 inhibitory activity (++++), comparable to that of CPT
Summary
Cancer is considered to be one of the most common diseases causing death and has been a huge health burden worldwide. For the purpose of discovering novel drug leads, a series of stilbene analogs containing a thiazole moiety were designed and synthesized in our previous work, and the results of Top1-mediated relaxation assays showed that all of them displayed a degree of Top inhibitory activity [28]. Among them, (E)-5-bromo-4-(2,6-difluorophenyl)-2-(2chlorostyryl)thiazole (Figure 2) showed a good Top inhibition of +++, which suggested that this novel scaffold could potentially lead to a new class of non-CPT Top inhibitors. It is our purpose to expand the structural diversity of these types of stilbene analogs and to study their potential anticancer activity. A variety of stilbene analogs (6–37, Figure 2) composed of a 4-(4-halophenyl)thiazole and a substituted phenyl ring were designed and synthesized, and subsequently their Top inhibitory activity and cytotoxic activity against two different cancer cell lines were evaluated for anticancer potential. The preliminary relationship between structure and activity and the study of their molecular docking are discussed
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