Synthesis of Benz［f］indole-4, 9-dione derivatives and Evaluation on their cytotoxic activity

Abstract

2-Chloro-3-(α-cyano-α-ethoxycarbonyl-methy1)-1,4-naphthoquinone(A),2-chloro-3-( diethoxycarbonyl-methyl)-naphthoquinone-4,9-dione(B),2-Chloro -3-(1-diethoxycarbonyl-ethyl)-1,4-naphthoquinone(C)를 출발 물질로 하여 2번 위치에amine, hydroxy, ketone기로 치환된 benz[f]indole-4,9-dione 유도체를 합성하였다. 출발 물질 A, B, C와 여러 종류의 지방족아민 또는 방향족아민을 반응시켜 2-amino-3-ethoxycarbonyl-N-substituted-benz[f]indole-4,9-dione 유도체 [A -I ( a-j ) ] , 2-hydroxy- 3- ethoxycarbonyl -N-substituted -benz[f]indole -4,9- dione 유도체[B-(a-1)],3-ethoxycarbonyl-3methyl-N-substituted-2,3-dihydro-benz[f]-indole-2,4,9-trione 유도체[C-(a-d)]를 얻었다. 일반적으로 지방족아민과의 반응에서는 triethylamine이 없어도 분자내 고리화 반응이 진행되었으나, 방향족아민과의 반응에서는 분자내 고리화 반응이 진행되기 위해서는 반드시 triethylamine이 촉매로써 필요하였다. 이와 같이 합성된 화합물들의 세포 독성 효능은 A459 (human lung), SK-OV-3(human ovarian), SK-MEL-2 (human melanoma), XF498 (human CNS), HCT 15(human colon)의 tumor cell line에 .SRB(Sulforhodamine B) assay로 측정하였으며, 대체적으로 2번 위치에 hydroxy기가 존재할 때보다는 amine기 또는 ketone기가 존재할때 세포 독성 효능이 더 높았다. 많은 화합물들이 SK-OV-3 (human ovarian)와 XF498(human CNS)에 대하여 높은 효능을 나타낸다는 결과를 얻었다.;Reactions of 2,3-dichloronaphthoquinone(Ⅰ) with ethyl cyanoacetate, diethyl malonate, and diethyl methyl malonate under the different conditions gave the starting materials, 2-chloro-3-(α -cyano- α -ethoxycarbonyl-methyl)-1,4-naph-thoquinone (A), 2-chloro-3- (diethoxycarbonyl-methyl) -1,4-naphthoquinone (B), and 2-chloro-3-(1- diethoxycarbonyl ~ ethyl)-1,4-naphthoquinone (C) respectively. 2-Amino-3-ethoxycarbonyl-N-substituted-benz[f]indole-4,9-dione derivatives[A-I(a-j)] were obtained when 2-chloro-3-(α-cyano-α-ethoxycarbonyl methyl) -1,4-naphthoquinone(A) was reacted with various amines (cyclopropyl-amine, 2-methoxyethylamine, 3-hydroxypropylamine, n-butylanune, trans-4-amino - cyclohexanol, 4- ethylaniline, 3,4- firnethylaniline, m - toluidine, m - ani sidine,and 3,4- (methylenedioxy)aniline). Reactions of 2-chloro-3- (diethoxycarbonyl-methyl) -1,4-naphthoquinone(B) with various amines (ethanolamine, 2-chloro-ethylamine, cyclopropylamine, 2- methoxyethylamine, furfurylamine, cyclohexylamino, trans-4-anuno-cyclohexanol, f-toluidine, 1,4-phenylenediamine, m-toluidine, m-anisidine, and 3,4-(methylenedioxy)aniline) gave B~hydroxy-3ethoxyc arbonyl - N- sub stituted -benz (f) indole -4,9- dione derivatives [B - ( a-1) ]. Fur-thermore, 2-chloro-3- (1- diethoxycarbonyl-ethyl) -1,4-naphthoqvinone(C ) wasreacted with cyclopropylamine, 2-methoxyethylamine, trans-4-amino-cyclo- (이후원문누락)