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標題: | 設計與合成具抗癌潛力之醯胺基及胺基甲醯基蒽醌類化合物 Design and Synthesis of Amido- and Carbamoyl- anthraquinones as Potential Antitumor Agents |
作者: | Wan-Ru Chen 陳婉茹 |
指導教授: | 忻凌偉 |
關鍵字: | 蒽,醌,類化合物,抗腫瘤, anthraquinone,Antitumor, |
出版年 : | 2005 |
學位: | 碩士 |
摘要: | 很多抗癌藥物具有很好細胞毒殺效果但卻沒有選擇性,增加抗癌藥物對DNA序列的選擇性可能可以減低毒性以及其他副作用。像 ametantrone 和 mitoxantrone 這類化合物抗癌方面已使用了很久的時間,有平面的蒽醌骨架的mitoxantrone 現在仍是臨床用藥。具有蒽醌類平面骨架的對於DNA的識別及結合是必須的而且在結合上DNA後進一步影響DNA的正常功能,例如轉譯RNA及複製DNA。而且這些嵌入DNA的分子可能可以辨識某些特定的鹼基對。為了改善對DNA親和力以及選擇性,設計以及平行合成蒽醌骨架這一系列化合物。我們保留了 mitoxantrone 具平面特性的三環骨架以及2-(aminoethyl)amino側鏈來接上各種胺基酸。接上的胺基酸側鏈可以對DNA產生離子作用力來加強對DNA的親和力。然而,胜肽骨架並不穩定容易被蛋白酶水解。近來在仿胜肽中很多應用了胺基甲醯基骨架替換醯胺基骨架。我們還原胺基酸並導入了 carbonyloxy 基團,再將 carbonyloxy 單體接到蒽醌骨架上,並且嘗試發展一個簡單的合成方式以便用來進行平行合成一系列具有胺基甲醯基側鏈的蒽醌類化合物。一些新的蒽醌類衍生物在人類癌細胞株上表現有不錯的細胞毒殺效果。 Most antitumor agents are highly cytotoxic but not selective. Increasing the lignad selectivity to specific DNA sequences may reduce their toxicity and other adverse effects. Drugs containing 9,10-anthracenedione, such as ametantrone and mitoxantrone, have been used as anti-tumor agents for a long time. Now mitoxantrone, which contains a planar anthraquinone skeleton, is a clinically useful antitumor agent. The planar characteristics of the core structure 9,10-anthracenedione are necessary for molecular recognition and binding into the base pairs of DNA helix to affect transcription and replication processes of the cell . This intercalative interaction may serve as an anchor for intercalating drugs at specific sites of DNA base pair followed by cell-killing. With the aims to increase the DNA affinity and selectivity, a series of l,4-bis[(2-aminoethyl)amino] substituted9,l0-anthracenedione was designed and prepared by parallel synthesis. We reserve the planar characteristics of the core structure 9,10-anthracenedione,and the 2-(aminoethyl)amino of mitoxantrone. The 2-(aminoethyl)amino could be linked a variety of amino acids. The side chain amino acids will create ionic interaction with the ribose phosphates of the nucleic acids. Howevre, the peptide backbone is not stable to proteolytic degradation. Recently an increasing amount of attention has focused on the application of the carbamate moiety as a replacement for the amide bond in peptidomimetics. We reduced the amino acid to amino alcohol and introduced a carbonyloxy group. In order to introduce the carbonyloxy monomer to anthracqueinone skeleton, we are trying to develop a convenient general method for parallel synthesis. Several novel anthracqueinone derivatives showed significant cytotoxicoty against different houmor cancer cell lines. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/24299 |
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