Novel Acridine Derivatives As Top Ⅱ Or Top/HDAC Inhibitors

As one of the most dangerous diseases,human have paid great attention to cure cancer.Many targets had been discovered to treat cancer,such as DNA,protein kinase,topoisomerase,HDAC.DNA/DNA-related enzymes are one of the most effective and common used intracellular anticancer targets in clinic studies.With a conjugated planar structure,acridine and its derivatives have been used to target the DNA or DNA-related enzymes early.Though acridine showed great antitumor activities,the high toxicity are still a serious problem.In this paper,based on the previous study,a series of novel acridine derivatives have been designed and synthesized by computer-aided drug design,aimed at obtaining a series of novel acridines with good antitumor activity and low toxicity.Molecular docking indicated that azaacridine derivatives might displayed better Top II inhibition activity than the corresponding acridines,therefore the first part of this study was to design and synthesize 9 novel azaacridine derivatives.MTT assay suggested that all the compounds had good antiproliferative activity against K562,among which compound 9 displayed preferable antiproliferative activity in broad spectrum cancer cell lines with an IC50 value of 0.57μM against U937 cells,which was better than m-AMSA.In addition,compound 9 displayed low cytotoxicity against human normal liver cells(QSG-7701),the IC50(29.36 μM)of which was 3 times less than m-AMSA.Later study indicated that all the compounds displayed topoisomerases II inhibition activity at 50 μM.The representative compound 9 could bind with DNA and induce U937 apoptosis through the exogenous pathway.Since the combination of Top and HDAC inhibitors had a synergistic effect,the sencond part of this thesis designed and synthesized 11 novel acridine analogues as topoisomerases and HDAC bifunctional inhibitors.The MTT assay against U937 showed 9 kinds of compounds expressed IC50 lower than 5 μM except for compounds 8g and 8h,and compound 8c(IC50=0.9μM)and 16a(IC50=0.75μM)displayed comparable antiproliferative activity to the positive drug SAHA(IC50=0.72μM).The MTT assay showed the introduction of the motif of target HD AC to acridine could improve the antitumor activity of the compounds significantly.In vitro enzyme inhibition of HD AC results showed 11 compounds displayed better inhibition activity against HDAC6 than HDAC1.Among the 11 compounds,compounds 8a,8b,8c,8d exhibited better HD AC inhibition activity than SAHA and compounds 8a,8c,8d displayed IC50 under 10 nM.Topoisomerases inhibition assay demonstrated all the compounds expressed great inhibition for Top Ⅱ at 50 μM,and compound 12 and 16a had strong inhibitory activity for Top I at 100 μM.