Synthesis And Anti-Tumor Activities Of 2,6-Bis(Arylidene) Cycloalkanones

Anticancer drugs frequently used in clinical have more than 80 kinds at present. According to their source and mechanism, these drugs can be divided into six types: antimetabolites, radiosensitizer, hormone medicines., immuno- mod ulator, mitotic spindle inhibitor and DNA-targeted drugs which including alkylating agents, DNA minor groove binders and intercalating agents. The mechanism of DNA intercalating druges is to make gene frameshift mutation.Anthracycline antibiotics are typical DNA intercalating drugs, and acrid ines are the aza-derivate of anthracene( the tenth carbon atom of anthracene is substituted by nitrogen),so acridines is also belong to DNA intercalating agent.From the research to the derivate of 9-aminoacridine, the researcher found that amsacrine,4-(9-aminoacridine)methylaniline had antitumor activity, and some of the compounds had been used for antitumor drug .The recent research reported that the derivate of proflavine -1′,1″-(acridin-3,6-diyl)-3′,3″-dialkyldiureas displayed their antitumor activities through intercalation of DNA chain. 2,6-bis (aminophenyl- methylene) cycloalkanones have the same configuration with proflavine,but their biological and pharmacological action have never been reported.From the structure and configuration analysis, we have an initial presumption that 2,6-bis(aminophenylmethylene) cycloalkanones shoud have antitumor activity. So it is significant to carry out the research to 2,6-bis (aminophenylmethylene) cycloalkanones in order to develope a new drug with high potency and low toxicity.In this study, nine 2,6-bis (aminophenylmethylene) cycloalkanones had been designed and prepared,six of which are new compounds . Firstly, 2,6-bis (nitrophenylmethylene) cycloalkanones were prepared through condensation of aldehydes with cycloalkanones in [bmim][BF4] which is promoted by InCl3·4H2O. Treatments of 2, 6-bis (nitrophenylmethylene) cycloalkanones with Fe and NH4Cl produced the corresponding 2,6-bis(amino-phenylmethylene) cycloalkanones. The route needs gentle condition and the products are easy to be purified. To confim the structure of these compounds, we have used IR, MS, 1HNMR and HRMS, etc. Their antitumor activities on cultured K562,A549 and QGY-7701cells have been evaluated in vitro by MTT assay. Their results showed that 2, 6-bis (amino-phenylmethylene) cycloalkanones had significant antitumor activities.The antitumor activities of all the compounds became potent as the concentration is increasing.Among them,compound 2g has a potent antitumor activity on K562,A549 and QGY-7701 cell lines with IC50 2.76,6.34,5.78μg/ml respectively.The structure-activity relationships indicated that more potent inhibitory activities against three cancer cell lines were exhibited when the compounds containing methyl group at the position 4 of cycloalkanones ring. On the other hand, the introduce of chlorine group would decrease the anti-tumor activity.