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Synthesis of halogenated azulenes. synthesis of bleomycin models : metal binding moiety analogs

Title
Synthesis of halogenated azulenes. synthesis of bleomycin models : metal binding moiety analogs
Authors
이규연
Issue Date
1999
Department/Major
대학원 화학과
Publisher
이화여자대학교 대학원
Degree
Master
Abstract
Part A : 최근 레이저가 연구 및 산업용 또는 의료용으로 널리 쓰이게 되면서 레이저 기기에 핵심부품으로 많이 사용되는 비선형 광학 물질에 대한 관심이 높아지고, 비선형 광학 연구에 핵심적으로 필요한 새로운 비선형 광학 유기 물질 합성의 중요성이 부각되고 있다. 이에, electron delocalization에 의한 비선형 계수 값의 증가에 초점을 두어, 2-Halogenated Azulene Derivatives를 합성하고자 했다. 이 합성은 상업적으로 구하기 쉬운 Tropilidene (Cycloheptatriene)을 출발물질로 하였고, Tropylium Fluoroborate, Tropyl Ether, Tropone, 2-Chlorotropone, Diethyl 2-Aminoazulene-1,3-Dicarboxylate, Diethyl 2-Chloro(bromo) azulene-1,3-dicarboxylate, 2-Chloro(bromo)azulene-1,3-dicarboxylic Acid 의 중간 생성물을 거쳐서 최종 목적으로 하는 2-Chloroazulene, 2-Bromoazulene을 얻을 수 있었고, Halide Interchange Reaction을 통하여 2-Chloroazulene으로부터 2-Iodoazulene을 합성할 수 있었다. 각각의 전체 수득률은 14%, 12%, 12.3% 였다. Part B : 블레오마이신은 Streptomyces로부터 추출된 글리코펩타이드류의 항종양성 항암성 천연물로서, 이러한 생리 활성은 블레오마이신과 금속의 착화합물 형성에 의한 DNA의 산화 절단 방법에 기인한다고 추정되고 있다. 본 연구에서는 블레오마이신의 금속 착화합물 형성 부위를 모방한 유도체의 합성에 초점을 두었다. 이 합성은, 먼저 상업적으로 구하기 쉬운 Paraformaldehyde로부터5-Bromo(chloro)-2-Hydroxymethyl-4-Pyrimidine Carboxylic Acid를 형성한 후, 이 중간체에 금속과 킬레이트를 형성할 수 있는 반응물(Histamine, Ethylenediamine, 1,3-Diaminopropane)을 결합시키고자 하였다. 극성이 큰 아민기로 인해서 생성물의 정제에 많은 어려움이 따랐고, 그로 인해 Semi-purified된 생성물들만을 얻었다. ; Part A : Organic molecules with highly polarizable p-electrons are of great interest currently for their potential application in nonlinear optical (NLO) devices. Herein we synthesized halogenated azulene derivatives in search for new photo chemical study candidates. The synthesis began with commercially available cycloheptatriene (tropilidene). We finally synthesized 2-chloroazulene and 2-bromoazulene in overall nine and ten steps respectively via tropone, 2-chloro- tropone, diethyl 2-aminoazulene-1,3-dicarboxylate, diethyl 2-chloro(bromo)azu- lene-1,3-dicarboxylate, 2-chloro(bromo)azulene-1,3-dicarboxylic acid intermedia- tes. We also synthesized 2-iodoazulene in overall ten steps through halide interchange reaction from 2-chloroazulene. The total yields of these compounds are 14 %, 12 % and 12 %, respectively. Part B : Belomycin(BLM) is an antitumor antibiotic clinically used in treatment of squamous cell carcinoma, malignant lymphoma, and testis tumors. The drug was isolated from Streptomyces verticillus as a copper chelate by Umezawa and his co-workers in 1966, and the structure was shown to be glycopeptide consisting of an unusual hexapeptide and a disaccharide. The DNA cleavage with BLM or the biological effect is considered to be due to two chemical characteristics; DNA binding by the bithiazole-terminal amine moiety and the dioxygen activation by the β-aminoalanine-pyrimidine-β-hydroxyhistidine moiety. In our model study on the metal binding site of BLM, we demonstrated that the 5-methyl-6-aminopyrimidine, the β-aminoalanine and the β-hydroxyhistidine of BLM could be replaced by 5-bromo(chloro)pyrimidine, ethylenediamine (or 1,3-diaminopro- pane), and histamine(or ethylenediamin or 1,3-diaminopropane). The synthesis began with a commercially available paraformaldehyde. After formation of hydroxyacetimino ether hydrochloride, the ethoxy group of this compound was converted to amino group by ammonolysis. The resulting amine was treated with mucobromic acid (or mucochloric acid) to affoard 5-bromo(chloro)-2-hydroxymethyl-4-pyrimidine. After activation of 2,4-position of pyrimidine ring with thionyl chloride, dichlorides were treated with diverse compounds(ethylenediamine, 1,3-diaminopropane, histamine). Several bleomycin mimicked anlaogs [5-bromo(chloro)-2-ethylene diamino- methyl-4-pyrimidinehistamide, 5-bromo(chloro)-2-(1,3-diaminopropylmethyl)-4-pyrimidine histamide, 5-bromo(chloro)-2-ethylenediaminomethy l-4-pyrimidine ethylenediamide, 5-bromo(chloro)-2-(1,3-diami- nopropylmethyl)-4-pyrimidine-1,3-diaminopropamide) were synthesized, and we semi-purified these compounds by recrystalliztion or prep HPLC (C-18 column).
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