Design,Synthesis And Application Of Benzimidazole Acridine Derivatives

Cancer is a major crisis for human health,death rate of which is only less than cardiovascular and cerebrovascular diseases.As DNA topoisomerases(Topo)mediate DNA replication,transcription,etc.and poly(ADP-ribose)polymerases(PARP)play an important role in DNA repair system,the inhibition of the activity of both of them can cause synthetic lethality.Nowadays,the combination of Topo inhibitors and PARP inhibitors have entered clinic therapy and showed promising effect for anti-cancer treatment,however,no compounds with the ability to inhibit both Topo and PARP are reported.As the combination study has many shortcomings,such as high cost,drug-drug's interaction,etc.,the development of compounds with the ability to inhibit both of them is important.Based on rational design and computer-mediated drug design,we designed and synthesized a series of benzimidazole acridine derivatives as potent Topo and PARP inhibitors.In vitro experiment showed that all these compounds highly suppressed the activity of PARP-1,most of which displayed nomolar IC50 values.The IC50 of compound 7a could reached 91 nM and the reaserch of 7q proved benzoxazole-4-carboxamide as efficient site.In addition,most of the compounds synthesized could bind with DNA and inhibit the activity of Topo at 100 ?M and the reaserch of 7p proved acridine as efficient site.Moreover,most compounds displayed high antiproliferative activity against K562 cells with low micromolar or nanomolar IC50 values.What's more,most of the compounds showed moderate to good inhibitory activity against MCF-7 cells.IC50 value of the typical compound 7l was 3.6 ?M,which was superior to Olaparib(IC50=5.8 ?M).Further study indicated that most compounds synthesized had good fluorescent property,which can be potently used as fluorescent probes.The results indicated that the representative benzimidazole quinoline based compound 7q could bind with Ag+ and displayed “turn-on” fluorescent effect.More study suggested that 7q showed high selectivity for Ag+ detection and had good detection limit,which reached the standard for drinking water of WHO.Considering its application area,we tested Ag+ in tap water and the result proved that the probe can work in nature water sample as well.1H NMR and MALDI spectra indicated that the binding mode of 7q with Ag+ was dependent on the concentration of Ag+.