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Pyridophenazinedione과 Benzophenazinedione 유도체의 합성

Title
Pyridophenazinedione과 Benzophenazinedione 유도체의 합성
Authors
박세영
Issue Date
2001
Department/Major
대학원 약학과
Publisher
이화여자대학교 대학원
Degree
Master
Abstract
Quinone derivatives, substances known to have various biological activities, have been used in many pharmaceuticals for many years. Nucleophilic addition or nucleophilic substitution allows easy intramolecular ring closure during pharmaceutical synthesis. Of these derivatives, heterocyclic quinone containing, nitrogen especially has superior anti-cancer and biological activities, and therefore much research have been focused on this substance. 6,7-Dichloro-5,8-quinolinedione and 2,3-dichloro-1,4-naphthoquinone were reacted with arylamine (aniline, o-toluidine, m-toluidine, p-toluidine, m-anisidine, p-anisidine, p-ethylaniline, p-phenetidine, p-trifluoromethylaniline, p-trifluoro- methoxyaniline, p-bromoaniline, m-chloroaniline, p-chloroaniline, p-isopropoxyaniline, 2-bromo-4-methylaniline, 3,4-dimethylaniline, o-amino- benzoic acid, 3,4-methylenedi-oxyaniline, p-aminoacetophenone, N,N-dimethyl- p-phenylenediamine to synthesize 6-arylamino7-chloro-5,8-quinolinedione (A-Ia~q) derivatives and 3-arylamino-2-chloro-1,4-naphthoquinone (B-Ia~m) derivatives. 6-arylamino7-chloro-5,8-quinolinedione (A-Ia~q) derivatives and 3-aryl- amino-2-chloro-1,4-naphthoquinone (B-Ia~m) derivatives were reacted with NaN_3 (sodium azide) in DMF (N,N-dimethyl-foramide) at 90~100℃ to synthesize 6,11- dihydro-pyrido[2,3-b]phenazine-6,11-dione derivatives (A-IIa~q) and 6,11- dihydro-benzo[2,3-b]phenazine-6,11-dione derivatives (B-IIa~m). DNA-intercalation complex of heterocyclic compounds with cytidilyl-3',5'- guanosine[(CpG)_2] dinucleotide was modelled by computer aided molecular modeling and the results showed that it was possible to insert DNA dinucleotide. And thus we could expect anti-cancer effects from heterocyclic compounds.;Quinone계 유도체는 다양한 생리 활성을 갖는 화합물로 수세기에 걸쳐 의약품 등에 널리 사용되어 왔다. 또한 의약품 합성에서 친핵성 첨가반응(Nucleophilic Addition) 및 치환반응(Nucleophilic Substitution)에 의한 분자 내 고리화 반응으로 연결 고리 확장이 쉽게 일어난다. 그 중에서 질소를 포함한 heterocyclic quinone 유도체는 특히 항암 활성 및 생물학적 활성이 우수하므로 이에 대한 많은 연구가 진행되어 왔다. 6,7-Dichloro-5,8-quinolinedione과 2,3-dichloro-1,4-naphthoquinone을 방향족 amine류 (aniline, o-toluidine, m-toluidine, p-toluidine, m-anisidine, p-anisidine, p-ethylaniline, p-phenetidine, p-trifluoromethylaniline, p-trifluoromethoxyaniline, p-bromoaniline, m-chloroaniline, p-chloroaniline, p-isopropoxyaniline, 2-bromo- 4-methylaniline, 3,4-dimethylaniline, o-aminobenzoic acid, 3,4-methylenedi- oxyaniline, p-aminoacetophenone, N,N-dimethyl-p-phenylenediamine)와 반응시켜 6-arylamino7-chloro-5,8-quinolinedione (A-Ia~q) 유도체와 3-arylamino-2- chloro-1,4-naphthoquinone (B-Ia~m) 유도체를 합성한 후, DMF를 용매로 하여 고온에서 NaN_3 (sodium azide)와 반응시켜 분자 내 고리화 반응에 의한 6,11-dihydro-pyrido[2,3-b]phenazine-6,11-dione 유도체 (A-IIa~q)와 6,11- dihydro-benzo[2,3-b]phenazine-6,11-dione 유도체 (B-IIa~m)를 합성하는 연구를 수행하였다. 본 논문에서 합성한 Phenazinedione 유도체의 특징은 Pindur가 제창한 DNA- intercalator로서의 조건을 충분히 갖춘 구조 즉, carbonyl 원자단과 질소를 포함하고 3~4개 고리로 이루어져 있으며 평면의 구조를 갖는 특징을 나타내고 있다. 따라서 computer aided molecular modeling을 이용하여 cytidilyl-3',5'- guanosine [(CpG)_2] dinucleotide와 헤테로 고리 화합물들과의 DNA-intercalator complex를 modeling한 결과 DNA dinucleotide에 삽입이 가능하여 항암 효과를 나타낼 것으로 기대하였다.
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