Design,Synthesis And Bioactivity Of Acridines

Cancer is a deadly disease in the world,great efforts have been made to understand the cancer biology and develop the potential anticancer drugs.Among the current strategies for cancer treatment,chemotherapy remains the most mature and effective approach.DNA is considered to be one of the most promising targets for anticancer agents.Numerous compounds display their anticancer activity through DNA binding and their effectiveness depends on the mode and strength of the binding.The interaction between anticancer drugs and DNA can cause DNA damage in cancer cells and block cell division,thereby leading to cell death.As cancer cells exhibit high levels of topoisomerase activity and demonstrate remarkable sensitivity to DNA-targeted drugs,enormous anticancer drugs have been designed and synthesized which specifically target the interaction between DNA and topoisomerases.DNA recognition is a key stage of anti-tumor action,and for clinic effectiveness of drugs,such as anthracyclines,anthraquinones,and acridines,intercalation is a kind of interaction in the recognition of these biomolecules.Therefore,the finding of novel DNA intercalating agents has been considered as a practical approach and a large number of molecules have been evaluated intercalation properties.The acridine derivatives can interact with the double stranded DNA.Acridine analogues have anticancer activity based on DNA binding and topoisomerases inhibition.However,due to the side effects,resistance and low bioavailability,a few have entered into clinical usage and the mechanisms of action are not fully understood.Novel acridine derivatives are needed for effective cancer therapy.In this study,three series of acridine derivatives were designed and synthesized and their pharmaceutical activities and mechanism of action were evaluated.Most of compounds could effectively inhibit cancer cell growth in the cell viability assay,such as compounds 1,2,3,10,15 and 22,especially platinum-acridine hybrid agent 22 with nanomolar cytotoxicity.Their DNA binding mode and DNA affinity were detected by the spectroscopic methods.The chemical modifications were crucial for DNA affinity,thus optimizing anticancer activity.Compounds could induce cell apoptosis in a dose-dependent manner.The cell cycle was detected by flow cytometry,3-nitroacridine derivatives arrest cell cycle at G0/G1 phase,1,3-dimethyl-6-nitroacridine derivatives arrest cell cycle at G2/M phage,and PT-ACRAMTU analogues arrest cell cycle at G0/G1 phage.Three series of acridine derivatives demonstrated different effects on cell cycle,probably for their different DNA binding modes.Though acridine derivatives are considered as potential anticancer candidates,the application of acridine derivatives is limited due to its poor solubility.To solve this problem,the most effective compound 22 was selected and encapsulated into liposomes.PT@NPs were characterized in terms of particle size,morphology,drug loading capacity(DLC),encapsulation effiency(EE)and stability.In vitro triggered release showed that the release of the drug was steerable and the release rate was fast under low pH(<7.0)and high temperature(>T_m=41℃).PT@NPs have the potiential in drug delivery systems(DDS)for non-small cell lung cancer(NSCLC)therapy.In conclusion,several acridine derivatives were synthesized,and they exhibited excellent DNA binding affinity,considerable cytotoxicity and induced apoptosis in cancer cells.The results showed that searching for new DNA-targeting agents is a practical way to develop antitumor drugs.