Synthesis And Antitumor Activity Study Of Tumor-targeted Brefeldin A Prodrug

(+)Brefeldin A(BFA),a kind of 16-membered ring macrolide antibiotics,have been extensively studied as a potential anti-cancer drug due to its high effect and wide-spectrum anti-tumor activity.However,its development and application is limited by its imperfection,such as poor solubility,great toxic side effect.In order to overcome this problem and obtain high antitumor activity and tumor-targeting produrg,we have designed and synthesized m PEGylated/biotinylation BFA derivatives and reduction-sensitive BFA prodrug according to the active targeting therapy,the passive targeting therapy and the prodrug therapy.Thus,the following research were carried out in this thesis.First of all,according to the interaction of ligand and receptor,we designed and synthesized a novel biotinylated BFA(1-2)which will actively target to tumor;m PEGylated BFA(1-3)were designed and synthesized as passive targeted prodrugs according the enhanced permeability and retention effect(EPR);Compounds 1-4,1-5,1-6 were prepared with the guidance of multi-targeting drug delivery mechanism.Secondly,the cytotoxic activities experiments of compounds 1-2,1-3,1-4,1-5 and 1-6 against the He La,Hep G 2,A549,MCF-7 and RTE cell line were test in vivo,the results suggest that these compounds exhibit good anti-tumor activities in our measure range,especially,compound 1-4,1-5 and 1-6 show excellent result and tumor targeting.In addition,the reasons of tumor targeting were preliminary studied using the method of fluorescent tracer.At last,the reduction-sensitive BFA prodrug(1-7)containing the function of fluorescence monitoring and targeted release were designed and synthesized based on the mercapto-disulfide bond exchange reaction.The experiments of the fluorescence properties and cytotoxicity-test in vivo of 1-7 showed that the prodrug can release drug to prevent tumor growth and fluorescence to monitor under the reaction of GSH.