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Quinoxaline유도체 합성 및 항암성에 관한 연구 : synthesis and cytotoxicity of quinoxaline derivatives

Title
Quinoxaline유도체 합성 및 항암성에 관한 연구 : synthesis and cytotoxicity of quinoxaline derivatives
Authors
유희원
Issue Date
1995
Department/Major
대학원 약학과
Publisher
이화여자대학교 대학원
Degree
Doctor
Abstract
항암활성이 높을 것으로 기대되는 화합물들을 얻기위해서 6,7-dichloro-5,8-quinoxalinedione(6)과 친핵성 시약을 반응시켜 2-methyl-4,9-dihydro-1-H-imidazo[4,5-g] quinoxaline-4,9-dione(56) 유도체, 5,10-pyrazino[2,3-g] quinoxalinedione(73)유도체들과 질소, 황 및 산소 등을 포함한 헤테로고리 화합물들을 합성하였다. 화합물6과 o-pfenylenediamine, o-aminophenol, o-aminothiophenol, 2-aminopyridine, catechol, 4-methozy-1, 2-phenylenediamine, ethylenediamine, aminoethanol, aminoethanthiol 및 N-methylethylenediamine등의 방향족, 지방족 dinucleophile과의 반응에서는 angular 헤테로고리 화합물들을 얻었으나 화합물6과 diaminopropane과의 반응에서는 헤테로고리 화합물대신 아미노기가 치환된 화합물을 얻었다. 화합물6으로부터 6-acetamido-7-chloro-5,8-quinoxalinedione(53)을 합성한 후 암모니아, methylamine, ethylamine, isopropylamine및, aniline등의 아민계 화합물들과 반응시켜서 2-methyl-4,9-dihydro-1-H-imidazo[4,5-g] quinoxaline-4,9-dione(56)유도체들을 얻었다. 화합물 53과 4-bromoaniline을 반응시켜서 6-acetamido-7-(4-bromophenyl)-5,8-quinoxalinedione(64)을 얻은 후 이를 염기로 처리하여 imidazole계 화합물을 얻었으며 4-aminiphenol을 반응시킨 경우에는 헤테로고리 화합물을 얻지 못하였다. 또한, 6-aceramido-7-amino-5,8-quinoxalinedione(55)을 diazo화하여 1-H-triazo[4,5-g] quinoxaline-4,9-dione(69)을 얻었다. 화합물6으로부터 6,7-diamino-5,8-quinoxalinedione(71)을 합성한 후 glyoxal, 2,3-butanedione, 2,3-pentanedione, 3-4-hexanedione 및 benzil등의 diketone류와 고리화반응시킨 경우에는 5,10-pyrazino[2,3-g] quinoxalinedione(73)유도체를 얻었으며 화합물71과 1,4-dibromo-2,3-butanedione을 반응시킨 경우에는 dibromo기가 dehalogenation된 화합물을 얻었다. 본 논문에서 합성한 화합물들은 DNA-intercalator로서의 조건, 즉, planar한 3-4개의 고리로 형성된 구조이므로 computer-graphics-aided molecular modeling을 이용하여 cytidilyl-3’,5’-guanosine[(CpG)_2]dinucleotide와 헤테로고리 화합물들과의 DNA-intercalator complex를 modeling한 결과 DNA dinucleotide에 삽입이 가능하여 항암효과를 나타낼 것으로 기대하였다. 시험관내에서 human lung adenocarinoma(PC 14), human gastric adenocarcinoma(MKN 45) 및 human colon adenocarcinoma(colon 205)를 이용하여 세포독성 실험을 해본 결과 MKN45에 대해서 pyrido[1,2-a]imidazo[4,5-g] quinoxaline-6,11-dione(34), 2-methyl-4,9-dihydro-1-methyl-1-H-imidazo[4,5-g] quinoxaline-4,9-dione(57), 2-methyl-4,9-dihydro-1-isopropyl-1-H-imidazo[4,5-g] quinoxaline-4,9-dione(59), 2-methyl-4,9-dihydro-1-(4-bromophenyl)-1-H-imidazo[4,5-g] quinoxaline-4,-dione(65)과 2,3-diethyl-5,,10-pyrazino[2,3-g] quinoxalinedione (76)화합물들이 cis-platin이나 adriamycin보다 세포독성효과가 높았다. ; With the aim of obtaining compounds which might be expected to have cytotoxicity, series of 2-methyl-4,9-dihydro-1-H-imidazo[4,5-g] quinoxaline-4,9-dione(56), series of 5,10-pyrazino[2,3-g] quinoxalinedione(73) and heterocyclic compounds containing nitrogen, sulfur ad oxygen, were synthesized by condensation of 6,7-dichloro-5,8-quinoxalinedione(6) with nucleophiles. Reaction of compound 6 with aromatic, aliphatic dinucleophiles such as o-pfenylenediamine, o-aminophenol, o-aminothiophenol, 2-aminopyridine, catechol, 4-methozy-1, 2-phenylenediamine, ethylenediamine, aminoethanol, aminoethanthiol, N-methylethylenediamine yielded angular cyclinc compounds. But reaction of compound 6 with 4-nitro-1,2-phenylenediamine and 1,2-diaminopropane did not afford heterocyclic compound. Reaction of 6-acetamido-7-chloro-5,8-quinoxalinedione(53) which was obtained from compound 6, with amine such as ammonia, methylamine, ethylamine, isopropylamine, and aniline gave 2-methyl-4,9-dihydro-1-H-imidazo[4,5-g] quinoxaline-4,9-dione(56) derivatives. Reaction of compound 53 with 4-bromoaniline afford 6-acetamido-7-(4-bromophenyl)-5,8-quinoxalinedione(64) which was converted to 2-methyl-4,9-dihydro-1-(4-bromophenyl)-1-H-imidazo[4,5-g] quinoxaline-4,-dione(65) by treatment with base. When compound 53 was reacted with 1-H-triazo[4,5-g] quinoxaline-4,9-dione(69) was prepared by diazoation of 6-aceramido-7-amino-5,8-quinoxalinedione(55). 5,10-pyrazino[2,3-g] quinoxalinedione(73) derivative were produced by reaction of 6,7-diamino-5,8-quinoxalinedione(71) which was obtained from compound 6, with diketones such as glyoxal, 2,3-butanedione, 2,3-pentanedione, 3-4-hexanedione and venzil. Reaction of compound 71 with 1,4-dibromo-2,3-butanedione gave a dehalogenated compound. DNA-intercalation complex of heterocyclic compound with cytidilyl-3’,5’-guanosine[(CpG)_2] dinucleotide by computer-graphics-aided molecular modeling inserted in DNA dinucleotide well. So heterocyclic compounds prepared were expected to be cytotoxic. As the result of cytotoxicity test in vitro, pyrido[1,2-a]imidazo[4,5-g] quinoxaline-6,11-dione(34), 2-methyl-4,9-dihydro-1-methyl-1-H-imidazo[4,5-g] quinoxaline-4,9-dione(57), 2-methyl-4,9-dihydro-1-isopropyl-1-H-imidazo[4,5-g] quinoxaline-4,9-dione(59), 2-methyl-4,9-dihydro-1-(4-bromophenyl)-1-H-imidazo[4,5-g] quinoxaline-4,-dione(65)과 2,3-diethyl-5,,10-pyrazino[2,3-g] quinoxalinedione (76) are more active to MKN 45 than cis-platin and adriamycin.
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