Synthesis And Biological Activities Of Selenium Ethers Containing Quinazoline Ring

Quinazoline,fused with benzene ring and pyrimidine ring,occupies an important position in the nitrogen-containing heterocyclic system due to its unique structure type and abundant biological activities.The research of quinazoline derivatives is mainly to introduce various pharmacodynamic groups into the quinazoline skeleton,and screen out the target molecules with excellent biological activity for research in the field of medicine.Selenide can promote human health,especially in antioxidant,anti-tumor and enhance resistance.Organic selenides are more advantageous than inorganic selenides in terms of immune activation effects,showing low toxicity and being easily absorbed by the human body.Quinazoline and organic selenide exhibit a wide range of anticancer activities through a variety of mechanisms.The 4 position substituted atom extends from O,N,S to Se atom.The structure of quinazoline modified with selenoether group were symmetrical quinazoline diselenide and sodium quinazolin-4-diselenide compounds lead the synthesis of quinazoline structure compounds substituted by monoselenide.It is expected that quinazoline selenide compounds with good tumor suppressing activity and weak cytotoxicity will be selected.In this thesis,twelve novel selazoline-modified quinazolines,twelve quinazolines substituted by similar thioether groups and three extended quinazoline target compounds containing ether bond functional groups were designed and synthesized.There are 18 compounds not reported in the literature.The structures of all compounds were confirmed by IR,¹H NMR and ¹³C NMR.Optimized the reaction conditions of the intermediates:?1?explore the effect of the amount of formamide on the yield of the cyclized product,and screen out the optimal amount of solvent;?2?the effects of chlorinating reagents and reaction time on the yield of 4-position chlorinated quinazoline products were optimized.The target compound of quinazoline substituted with monoselenoether were regarded as the template reaction.Then the optimal reaction method was selected to synthesize the target compound of quinazoline modified by monoselenoether:nucleophilic substitution of quinazoline selenium sodium salt with halogenated hydrocarbon to obtain the final product.Improved reaction method of the target product of quinazoline modified with thioether group:using the"one-pot method"to synthesize quinazoline sulfide compounds in the green solvent PEG-200.Thiourea,treated as the sulfurizing reagentreacted with alkyl halide and 4-chloroquinazoline compounds.The MTT assay was used to evaluate the anti-A549 cell lines of 20 target compounds at 1?M and 10?M concentrations in vitro.The target compound showed abetter anti-tumor effect at a concentration of 1?M than the quinazoline structuremodified by diselenide and diselenide sodium.It also showed a small concentration dependence.At a concentration of 10?M,the seleno-modified quinazoline structure exhabited the best anti-proliferative activity when mono-substituted.Especially the6-chloro-4-benzylseleno-substituted quinazoline had an inhibitory rate of 67.8%.The inhibition rate was better than 62.8%of the control drug Gefitinib.Quinazoline sulfide compounds showed the best inhibitory activity of A549 cell line when they were not substituted,with an inhibition rate of 56.3%;The bis-substituted quinazoline structure with ether bond groups showed the most significant inhibitory activity in vitro,6,8-dichloro-4-ethyloxyquinazoline inhibition rate was 56.0%.Through the inhibitory activity test of the target product against A549 tumor cells in vitro,the compound6-chloro-4-benzylselenoquinazoline?21?was selected to have good anti-A549 cell line proliferation activities.It has the potential to develop anti-cancer drugs.