Synthesis And Microencapsulation Of Some Novel4-anilinoquinazoline Derivatives For Molecular Targeted Anti-cancer Drugs

4-anilinoquinazoline derivatives are highly active, and they show great bioactivity interms of antibiotics, antitumor and antivirus. Up till now, they have been widely used in tumortherapy as EGFR tyrosine kinase inhibitor. It is reported that more than1004-anilino-quinazoline derivatives have been launched on the market or begun to reach the clinical trials.In this dissertation, the author synthesized a series of novel4-anilinoquinazoline derivatives,and the anticancer activity of them has been measured and evaluated. Moreover, the authorprobed into microencapsulation technology for these compounds. The present study is of greatscholastic value, with the compounds shedding some lights on the development andapplication of anticancer drugs, and the research findings potentially being useful in thetherapy for malignant tumor and creating massive social benefits.To start with, the author chose3-chloro-4-methoxybenzenamine and4-chloro-6-iodo-quinazoline as reactants. N-(3-chloro-4-methoxyphenyl)-6-iodoquinazolin-4-amine wassynthesized via aromatic amine nucleophilic substitution reaction under the presence ofneutralizer. Then under the presence of both catalyst and neutralizer, seven novel4-anilinoquinazoline derivatives were synthesized via Suzuki coupling reaction ofN-(3-chloro-4-methoxyphenyl)-6-iodoquinazolin-4-amine with3-cyanophenylboronic acid,3-carb-amoylphenylboronic acid,3,4-dimethoxyphenylboronic acid,3-aminophenylboronicacid monohydrate,4-(Trifluoromethoxy)benzeneboronic acid,2-furanboronic acid and5-formylfuran-2-boronic acid, respectively. After that, the author chose the6-(3-aminophenyl)-N-(3-chloro-4-methoxyphenyl)quinazolin-4-amine among the sevencompounds as reactants for another experimental stage. Three amide group-containing4-anilinoquinazoline derivatives were synthesized via acyl reaction of6-(3-aminophenyl)-N-(3-chloro-4-methoxyphenyl)quinazolin-4-amine with acetic anhydride, trifluoroaceticanhydride and maleic anhydride, respectively. All the novel4-anilinoquinazoline derivativeswere characterized and tested with FT-IR,1H-NMR, MS and EA, which proved that they hadthe same structures with the original design.The study shows that, this series of compounds have prominent inhibitory effects in the proliferation of lung cancer cell lines A549, hepatoma cell lines Bel-7402, gastric cancercell lines SGC7901, nasopharyngeal carcinoma cell lines CNE2. And the results indicated thatall of them were of comparably good anticancer activity, especially that of SGC7901’s. It isnoteworthy that6-(3-aminophenyl)-N-(3-chloro-4-methoxyphenyl)quinazolin-4-amine poss-esses relatively high selectivity, great anticancer activity and comparably low biotoxicity forits IC50for many kinds of tumor cell lines reaches0.05-0.125mM. As a result, it has thepotential for further development into anticancer drugs.Moreover, the author made a comparison between two preparation methods in whichethylcellulose was used to encapsulate N-(3-chloro-4-methoxy-phenyl)-6-iodoquinazolin-4-amine. And the microcapsules were characterized and tested with FT-IR and SEM. Also, theauthor adopted orthogonal experimental design method to determine the influences of mixingspeed, core-wall ratio, churning time on the preparation of microcapsule. The results showedthat the order of priority was as follows: churning time> core-wall ratio> mixing speed. Theprocess worked the best when the mixing speed was1700rpm; core-wall ratio was1:6and thechurning time was3h. Under this condition, the microcapsules were at its best in shape,distribution of particle size and aggregation state. Meanwhile, the author had discussed thepreparation technics and releasing characteristic of ethylcellulose microcapsuleloading6-(3-aminophenyl)-N-(3-chloro-4-methoxyphenyl)quinazolin-4-amine. The results showedthat the microcapsules were at its best state when the churning speed was800rpm andcore-wall ratio was1:3, and the embedding rate and drug-loading rate were61.18%and15.29%, respectively. When the microcapsule was tested for its release property in simulatedgastric fluid, it showed great performance and within two hours, the releasing rate nearlyreached65%.