피리디노 [2,3,f]인돌 -4,9- 디온 유도체의 합성

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.