Design,Synthesis And Bio-evaluation Of Benzimidazole Derivatives As Topoisomerase ? Inhibitors

DNA Topoisomerase ?(Topo?)is an important enzyme involved in DNA replication,recombination,and repair.Due to its important role in cells,Topo ? has become an important target for anticancer drugs.Topo ? inhibitors can be classified into Topo ? poison and Topo ? catalytic inhibitors according to their different mechanism of action.Since the introduction of the Topo? agent represented by the anticancer drug etoposide,it has been widely used clinically,but there are serious risks of drug resistance and side effects.Studies have shown that Topo? catalytic inhibitors are more potent and less toxic than poisons,and catalytic inhibitors can antagonize the side effects of poisons.Therefore,the study of Topo? catalytic inhibitor is of great significance.Benzimidazoles have a wide range of biological activities,such as antibacterial,anti-inflammatory,anti-tumor,etc.Studies have shown that benzimidazole rings play a critical role in the antitumor activity of compounds.Pyrrolo[2,3-b]pyrazine are a class of compounds with important kinase inhibition and also contain DNA Topoisomerases.In addition,chalcone analogs have a variety of pharmacological effects,including anti-cancer,anti-oxidant,anti-inflammatory and anti-infective activities,and studies have shown that their ?,?-unsaturated ketones are key pharmacophores.It is possible to find novel Topo ? catalytic inhibition by splicing benzimidazole with Pyrrolo[2,3-b]pyrazine or chalcone.Based on the previous research of the research group and the literature research,the design,synthesis and biological activity of two kinds of compounds,a series of benzimidazole pyrrolo[2,3-b]pyrazine compounds and benzimidazole chalcone compounds,were carried out with Topo? as the target and mechanistic studies,expecting to discover new Topo? catalytic inhibitors of antitumor drugs.The specific content and results are as follows:1.Topo ? catalytic inhibitors in the previous research group were used as lead compounds,and various benzyl groups were introduced into the imidazole ring of benzimidazole pyrrolo[2,3-b]pyrazine.sixteen benzimidazole derivatives were designed and synthesized.The benzimidazole compound was introduced into the chalcone fragment,and twenty one benzimidazole chalcone compounds were designed and synthesized.2.The synthesized benzimidazole pyrrolo[2,3-b]pyrazine were subjected to Topo ? inhibitory activity and antitumor cell proliferation activity.The compounds have no significant Topo ? inhibitory activity at high concentrations(50 ?M).Cytotoxicity experiments showed that these compounds have a good inhibitory effect on the proliferation of multiple tumor cells,especially for HepG2 cells.The cell clonogenic assay and the cell migration assay showed that the compounds could effectively inhibit the colony forming ability and migration ability of HepG2 cells.The apoptosis experiment indicated that the compounds showed it can induce apoptosis of HepG2 cells.It is indicated that the modification of the imidazole ring of benzimidazole pyrrolo[2,3-b]pyrazine directly affects the catalytic inhibition of Topo ?.The benzyl modified compounds lose the catalytic inhibition of Topo?,but its mechanism of good toxic effect on tumor cells.Still to be studied.3.The synthesized benzimidazole chalcone were subjected to Topo ? inhibitory activity and antitumor cell proliferation activity.Cytotoxicity experiments showed that these compounds have a good inhibitory effect on the proliferation of multiple tumor cells,especially for A549 cells.The cell clonogenic assay and the cell migration assay showed that the compounds could effectively inhibit the colony forming ability and migration ability of A549 cells.The apoptosis experiment indicated that the compounds showed it can induce apoptosis of A549 cells.The Topo ? inhibitory activity of the benzimidazole chalcone compounds has a good correlation with the anti-tumor cell proliferation activity,further indicated that the compound inhibits theproliferation mechanism of tumor cells and is associated with the Topo ? inhibitory activity.The Topo ?-DNA cleavage reaction assays.and the Topo I-mediated DNA unwinding experiment proved that the compounds are a kind of non-embedded type Topo ? catalytic inhibitor.In summary,a total of 37 benzimidazoles were designed and synthesized,including 16 benzimidazole pyrrolo[2,3-b]pyrazine and 21 benzimidazole chalcone compounds.The benzimidazole pyrrolo[2,3-b]pyrazine have a loss of inhibitory activity against Topo ?,but still have good anti-tumor cell proliferation activity.The benzimidazole chalcone compounds have good Topo? inhibitory activity and anti-tumor cell proliferation activity.Further studies of anti-tumor Topo? inhibitors provide theoretical and experimental evidence.