The Synthesis Of Novel Thiophene [2,3-6][1,8] Naphthyridine-4-ketones And Their Antitumor Activity

This dissertation is divided into three chapters, we designed and synthesized novelthiophene[2,3-b][1,8]naphthyridine-4-ketones, and the preliminary antitumor activity ofthese compounds was studied.In chapter one, the biological activity of quinoline-fused heterocycles and1,8-naphthyridine-fused heterocycles was introduced; The syntheses of thieno[2,3-b]quinolineand thieno[2,3-b][1,8]naphthyridine were reviewed and the objective and significance ofthis research were introduced.The structures of quinoline and1,8-naphthyridine are similar. So they may have similarbioactivity according to principles of bioisosteric replacement. Quinoline-fused heterocycleswere reported to have antitumor, antimicrobial, antiinflammatory, antiallergic effects andetc.while,1,8-naphthyridine-fused heterocycles due to synthetic limitation, have not beenthroughtly studied. Therefore, development of synthetic method leading to diversified1,8-naphthyridine-fused heterocycles should aid the study of their activity.Thieno[2,3-b][1,8]naphthyridines may exhibit similar bioactivities of the thieno[2,3-b]quinolines, and prepared by similar synthetic methods. The key steps are to synthesizepyridine ring from multisubstitudied nicotinic acid, the subsequent the thiophene ringclosure.There are four synthses of thieno[2,3-b]quinoline and thieno[2,3-b][1,8]napthyridinefrom sulfur starting materials:1,2-mercaptoacetic acid or2-mercaptoacetate;2, inorganiccompounds Na₂S or P₂S₅;3, thiourea;4, isothiocyanates. However, these methods havesome disadvantages. For example, materials are smelly or toxic; molecular diversity islimited, the rount is long and so on.We intend to synthesize the2-amino thiophene ring by Gewald reaction, then synthesizethe priding-4-one by cyclization with alkyl halide. Finally, we synthesize thiophene[2,3-b][1,8]naphthyridine-4-ketone. This expeimental rount is novel and simple. The products canbe readily derivatized to a library of thieno[2,3-b][1,8]naphthyridines.The second chapter introduces the design and synthesis of thiophene[2,3-b][1,8]naphtha-yridine-4-ketone and their derivatization. Firstly,（2-aminothiophen-3-yl）（2,6-dichloropyridin-3-yl）methanone2-5was synthesizedfrom3-（2,6-dichloropyridin-3-yl）-3-oxopropanenitrile2-3by Gewald reaction.Then, in thepresence of NaOH in DMF, compound2-5reacted with alkyl halides to form the ringclosure products thiophene [2,3-b][1,8]naphthyridines2-8. Finally, to increase the diversityof the family compounds,7-Cl of compount2-8was substituted by amino, alcokol, thiol andetc. Therefore, we developed a convenient, simple method to synthesize multisubstitutedthiophene[2,3-b][1,8]naphthyridine-4-ketone compouds.This third chapter gave a brief introduction to the antitumor activity of thiophene [2,3-b][1,8] naphthyridine-4-ketones and their derivatization products on Hela cell line.Firstly, we screened for the antitumor activity of compounds2-8. The inhibitory rate ofHela cell growth was about12%-25%, and showed that compounts2-8have no significantantitumor activity. Then, we discussed the structure-activity relationship of2-10. We findthat position7of2-10must be ring with hydrophilic groups, for example, the IC50of2-10cis13.0μM; position9of2-10must be ring with hydrophobic groups, for example, the IC50of2-10s and2-10u are12.8μM and12.5μM respectively。...