Design,Synthesis And Study Of Novel Quinazoline Antitumor Drugs

The treatment and cure of malignant tumors has always been one of the major problems in the scientific and medical circles,and it is also a research hotspot.Currently,molecular targeted therapy has become a popular treatment for cancer,Gefitinib,the most classical quinazoline antitumor drug,which is used in the clinical treatment of NSCLC with EGFR mutation.Quinazoline skeleton structure has a wide range of biological activities.The structure of quinazoline compounds is of great significance for further research.In this paper,15 new target compounds were designed and synthesized by studying the structure-activity relations of quinazoline drugs.4-[(substituted phenyl)amino]-7-methoxy-6-ol(5a-5h)were prepared from 3,4-dihydro-7-methoxy-4-oxoquinazoline-6-yl acetate(1)by chlorination,amination and hydrolysis;The intermediates 5a-5h are further subjected to halo--genated hydrocarbon etherification to obtain the target compounds N-(substituted phenyl)-7-methoxy-6-(3-morpholinepropoxy)quinazolin-4-amine(8a-8h);N-(substituted phenyl)-7-methoxy-6-[3-(4-methyl-piperazine-1-yl)propoxy]quinazoline-4-amine(8i-8o)were produced from intermediates 5a-5g by halogenated hydrocarbon etherification and amination.The structures of related intermediates and target compounds were confirmed by IR and ~1H-NMR.The results through preliminary screening of partial target compounds for antitumor activities by MTT method,showed that the inhibition rate of target compound 8c(38.45%)on breast cancer MCF-7 cell lines was slightly higher than that of the positive drug gefitinib(37.26%).For pancreatic cancer SW-1990 cell lines,7 target compounds showed better inhibitory effect(The inhibition rates of 8b,8d,8e,8h,8j,8k,8l were 27.98%,27.48%,17.92%,26.55%,31.04%,42.21%,19.42%,respectively)than gefitinib(13.25%).