Study On Design, Synthesis And Antitumor Activity Of Salicylanilide Esters

Human health has been seriously threatened by malignant tumor. With thedevelopment of molecular biology, people gradually recognized that tumor, like allcomplex diseases, is multivariate. And consequently, single target drugs cannot blockthe signal transduction of tumor cells，even is prone to produce drug resistance. This hasled to an increasing interest in the development of multitarget antitumor drugs.In order to find multitargeted antitumor agents, we used the combination theoryand the principle of pro-drug to design the target compounds with valproic acid orbutyric acid structure, the histone deacetylase inhibitor, and niclosamide structure, theJAK-STAT3signal pathway inhibitor. The target compounds were expected to playmultitarget activity in vivo. The synthesized compounds were evaluated for their cellproliferation inhibition in vitro, and compound6j was selected for its chemical stabilityand pharmacokinetics.Concise synthesis route was adopted in this thesis, twenty two salicylanilide esterswere synthesized. Their structures were confirmed by1H NMR,13C NMR, ESI-MS andIR.In vitro chemical stability and in vivo pharmacokinetics of the target compound6jshowed that: it has certain stability in vitro, and can be hydrolyzed into niclosamide andvalproic acid in vivo.Anti-tumor activities of the target compounds against K562, A549, A431cells invitro were investigated by MTT assay and SRB assay. The results indicated that thecompounds6h,6i,6j,7g,7j,7l were found to have better activity than Gefitinib, andcomparable to niclosamide, which are worth to be intensively studied further.