Synthesis And Anti-tumor Activities Of 8H-phthalazino[1 2,b]-quinazolin-8-ones Derivatives

Heterocyclic compounds containing phthalazine unit and polycyclic alkaloids containing quinazolinone unit show a variety of pharmacological activities,such as anti-tumor,anti-bacterial,anti-inflammatory,and so on.It is quite significant to design,synthesize these novel compounds and study their biological activities in drug development.This thesis is divided into three chapters:In the first chapter,synthesis of three alkaloids containing phthalazine unit,including tryptanthrin,rutaecarpine and luotonin A and their bioactivities were reviewed.The design ideas and research contents of this thesis were introduced briefly.In the second chapter,a novel and convenient procedure for the synthesis of 8H-phthalazino[1,2,b]quinazolin-8-ones derivatives was introduced.Firstly,anthranilic acid reacted with triphosgene to give lactone,then via hydrazinolysis,condensation,chlorinated and finally introduced hydrophilic side chains in five steps to give twenty five 8H-phthalazino[1,2,b]quinazolin-8-ones derivatives.Their structures were confirmed by NMR,HRMS and X-ray crystallography.In the third chapter,anti-cancer activities of twenty five compounds were investigated.MTT assay indicated that compounds possessed good to excellent inhibitory activities against the proliferation of five kinds of cancer cells in vitro,including T24(bladder cancer),NCI-H460(lung cancer),MGC-803(gastric cancer),HepG2(liver cancer)and Hela(cervical cancer);among which 6a～6e,7a～7e showed great inhibitory activities against the five cancer cells,with the IC50 ranging from 2.12 to 32.15 μmol/L.6c and 7c were studied the influence on T24 and MGC-803 cells by flow cytometry technique,the results showed that compound 6c and 7c can block the T24 and 803 cells in G2 phase,and they can promote the apoptosis of T24 and 803 cells.