Synthesis And Antitumor Activity Of 4-tert-butyl-5-azole-2-amino Thiazole And Amide Derivatives

Cancer has became one of the world leading causes of death.Although chemotherapy is one of the most important means to cure cancer presently,its side effects capture the attention.Therefore,there is a great need to design,screen,and identify new agents for the chemotherapy of cancer,and develop more effective drugs with low-toxicity.Aurora kinase is a new discovered target in recent years,which has been proved to be strongly associated with tumorigenesis.Aurora kinases are a family of serine/threoning kinases whose structures and functions are highly conserved in different model organisms.They play significant roles in many events during cell mitosis,such as centrosome maturation,separation,spindle assembly and maintenance,chromosome segregation)cytokinesis.Aurora kinase is activated only in mitosis,and show low expressions in those non-proliferation cells.So aurora kinase inhibitors is a kind of potential new targets for cancer treatment because of its higher selectivity.Recent years,many reports of aurora kinase inhibitors have mentioned thiazole amine groups.Thiazole amine group is a kind of significant active groups which have show extensive biological activities.Herein we used 1-(3-chlorophenyl)-3-(5-(2-(thieno[3,2-d]pyrimidin-4-amino)ethyl)thiazol-2-yl)turea as the lead compound,designed and synthesized two series of compouds:N-bromo-4-(tert-butyl)-2-amide]thiazole(6)and N-[4-(t-butyl)-5-(1H-imidazol-1-yl)-2-amide]thiazole(8),and tested their antitumor activity in vitro.The compounds N-(5-bromo-4-(terr-butyl)-2-aimide)thiazole(6)and N-[4-(tert-butyl)-5-(1H-imidazol-1-yl)-2-amide]thiazole(8)were studied for their cytotoxicities against Hela cell lines,as determined by MTT assay.The antitumor assay shows that the series of compounds exhibited moderate to strong antitumor activities against Hela cell lines.Compouds 6c,6d,6n,6o,8e,8o showed strong cytotoxic activities against Hela cells with IC50 values of 0.019、0.041、0.031、0.036 and 0.039 mmol/L,respectively,which were equivalent to that of Cisplatin(IC50 0.036 mmol/L).The inhibition activity of compound 2i(IC50 0.003mmol/L)against Hela cell was better than Cisplatin,which was identified as the most promising candidate for further study.Structure-activity relationship study show that thiazole ring substituted by bromine has a higher antitumor activity than imidazole.The activity of benzamide is generally higher than the activity of fatty amide,especially when the benzamide is substituted on C3 and C5.An improved process has been developed for bromination.The optimal synthetic condition of 4-tert-butyl-5-(1,2,4-triazol-1-yl)-2-aminothiazole(3)was obtained by using single factor experiment method,choosing NaBr-H2SO4-H2O2 as brominate system.The more rate of the reactants is n(3,3-dimethyl-1-(1,2,4-triazol-1-yl)-2-butan-one):n(sodiumbromide)n(sulfuric acid):n(hydrogen peroxide)=1.0:1.1:0.825:1.75,and the better condition is reacting under 65℃ for 3.0 h with CCl4 as solvent.NaBr can be recovered and reused.The overall yield of compound 3 was 86.9%,and the recovery rate of bromine was 70.0%.Compared to other bromination process,the process mentioned here has certain advantages,such as high reactivity,good selectivity,high utilization rate of bromine,which lays a foundation for implementation of industrialization.