A Study On Synthesis Of Tetrahydro-1H-pyrido[2,3-b]indol Derivatives And Their Biological Activities

In this thesis,we reported that synthesis of hexahydro-1H-pyrido[2,3-b]indol derivatives using substituted aniline as starting material via Grignard,Michael addition,amidation and reductive cyclization reactions.Then we selected those compounds to study in vitro anti-tumor activity,in order to get better active compounds.Firstly,we synthesized 9 isatins,which are initial substrates,through the Sandmeyer isonitroso acetyl aniline Isatin synthesis method.Secondly,we got 31 intermediate 3-aryl（or alkyl）-N-Boc（or methyl）indole compounds,coupled with Grignard,Michael addition,amidation,reductive cyclization reactions.Finaly,through the amidation and Al Li H₄ cyclization reaction,we got 32 tetrahydro piperidine[2,3-b]indole derivatives.What’s more,optimization of the reaction was conducted by screening the catalyst,solvent,basic conditions and reaction time and the yielding productivity has reached to 92%.The route of this synthesis was simple and efficient,and the reaction conditons was mild,by which we have got 28 hexahydro-1H-pyrido[2,3-b]indol-2-one scaffolds together with 4 hexahydro-1H-pyrido[2,3-b]indol scaffolds.These synthesized compounds were tested anti-tumor activity in vitro with the method of MTT.And we used the clinical anticancer drug cisplatin as a positive control to test its effect on PC-3（human prostate cancer）,A 549（non-human small cell lung cancer）,K 562（human chronic myelogenous leukemia）activities.The results showed that these compounds（4i,4k,4o,4q,4r,4s,4t,4u,4z,4ad,4af）had strong cytotoxic for K 562.Among them 4i,4o,4q,4r,4u also had great activities to cells PC-3,A 549.Compound 4i and 4o had near or higher activities to three cells K 562,PC-3,A 549 and near or higher than the positive control drugs cisplatin.There compounds（4i,4o,4r）have notable activities for（human chronic myelogenous leukemia）K 562.The results of the anti-tumor activity in vitro showed that:hexahydro-1H-pyrido[2,3-b]indol-2-one scaffold compounds have anti-tumor activities.Among them hexahydro-1H-pyrido[2,3-b]indol-2-one scaffolds have higher activity than the hexahydro-1H-pyrido[2,3-b]indol scaffolds.This shows that the presence of two carbonyl groups is advantageous;it can increase its toxic effects on cells.In addition,increasing the lipophilicity of the compounds will help improve the activity.The piperidine-tetrahydro[2,3-b]and indol-2-keto-derivatives can be used as Lead compounds in the study of antitumor drugs.