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피리디노 [2,3,f]인돌 -4,9- 디온 유도체의 합성

Title
피리디노 [2,3,f]인돌 -4,9- 디온 유도체의 합성
Other Titles
Synthesis of Pyridno [2,3,f]indole-4,9-dione derivatives
Authors
신성희
Issue Date
1993
Department/Major
대학원 약학과
Keywords
피리디노디온 유도체Pyridno
Publisher
이화여자대학교 대학원
Degree
Master
Advisors
서명은
Abstract
항암제로 약효가 뛰어난 Streptonigrin은 독성이 강한 단점이 있어서 많은 학자들이 새로운 항암제의 개발을 시도하고있다. 최근 보고된 Johnson연구진의 보고에 의하면 Streptonigrin의 모핵인 Quinoline-5,5-dione유도체가 강한 항암효과를 가지고 있는것으로 알려졌다. 본 실험에서는 분자내 고리화 반응을 통해 Quinoline-5,8-dione을 모핵으로 한 Pyridino[2,3, f]-indole-4,9-dione유도체와 기타 heteroaromatic compound를 합성하였다. 즉, 6,7-Dichloro-quinoline-5,8-dione을 NH_(4)0H 존재하에서 α-cyanoethylester와 반응시켜 6-( α -cyano- α -ethoxycarbonyl -methyl )-7-chloro-quinoline-5,8-dione(compoundⅠ )을 합성하였다. 이를 지방족아민과 반응시켜서 2-amino-3-ethoxycarbonyl-N-alkyl-pyridino[2, 3, f] indole-4,9-dione 유도체(compoundⅡa-e)를 얻었으나 방향족아민과의 반응에서는 분자내 고리화 반응이 일어나지않고 친핵성 치환 반응만이 일어난 6-(α-cyano-α-ethoxycarbonyl-methyl)-7-arylamino-quinoline-5,8-dione유도체(compoundⅢa-e)를 얻을수 있었다. 친핵성 치환반응후에 분자내 고리화 반응이 진행되어 얻어진 2-amino-3-ethoxycarbonyl-N-aryl-pyridino[2, 3, f] indole-4,9-dione유도체(compoundⅣa-b)는 triethylamine이 base로 작용할 경우에만 합성되었다. 기타 heteroaromatic compound는 6,7-dichloro-quinoline-5,8-dione을 각종 아민류와 반응시켜서 얻었다. 또한, 위와 같이 합성된 화합물들의 항암제로서의 효능을 computer-graphics-aided methods of molecular modeling을 통해서 예측해 보았고 MTT assay를 실시하여 실험관내에서의 항암효과를 살펴보았다.;Streptonigrin is an antitumor agent that has been limited use because of its toxicity. Developing new anticancer reagent, it was found that quinoline-5,8-dione derivatives, the moiety of Strptonigrin, have strong antitumor action. In this study, the pyridino[2,3,f]indole-4,9-dione derivatives and other heteroaromatic compounds with quinoline-5,8-dione were synthesized. 6,7-dichloroquinoline-5,8-dione was reacted with α-cyanoethylester in ammonia solution to yield 6-(α-cyano-α-carboxyethyl-methyl)-7-chloro-quinoline-5,8-dione(compound I). When this compound was reacted with some alkylamines 2-amino-3-ethoxycarbonyl-N-alkyl-pyridino[2,3,f]indole-4,9-diones(compounds Ⅱa-e) were prepared. However, when it was treated with the arylamines, only 6-(α-cyano-α-carboxyethyl-methyl)-7-arylamino-quinoline-5,8-diones(compound Ⅲa-d) were obtained without furthur cyclization. The ring-closed compounds, 2-amino-3-ethoxycarbonyl-N-aryl-pyridino[2,3,f]indole-4,9-diones(compound Ⅳa-b) were prepared when triethylamine was employed as a base for the reaction of 6-(α-cyano-α-carboxyethyl-methyl)-7-chloro-quinoline-5,8-dione and arylamines, other heteroaromatic compounds(compound Ⅴa-b, Ⅵ, Ⅶ) were synthesized when 6,7-dichloroquinoline-5,8-dione was treated with several kinds of amine. We predicted its antitumor action using computer-graphics-aided-methods of molecular modeling and tested anticancer ability with MTT assay.
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