- 作者: 張鵬
- 作者服務機構: 國防醫學院藥學系
- 中文摘要: Ametantrone及Mitoxantrone是類化合物,在動物實驗及臨床研究中具有顯著的制癌活性,Ametantrone可由Leucoquinizarine與2-(2-乙基胺胺基)乙醇反應,再經氧化製得。製備Mitoxantrone所須之原料化合物無法取得,因此本研究發展出經由Chrysazin合成Mitoxantrone之途徑。製備步驟啟於硝化Chrysazin,產物經還原後可得1,8-雙羥-4,5一雙胺,經由還原性水解反應,可製得leuco-1,4,5,8一四羥,以此物為原料仿合成Ametantrone步驟可得Mitoxantrone,總產率32%。合成的抗癌經光譜分析法鑑定,其結構業經高解析核磁共振譜的精細解釋証實。Mitoxantrone水解產物之一,同時也是合成過程的副產物,經鑑定是一類化合物。安全性試驗係以老鼠經尾靜脈注射不等劑量Mitoxantrone完成,經計算LD為57mg/kg。合成的Mitoxantrone經由實驗動物白血癌測試,效價與文獻報告相當。
- 英文摘要: Ametantrone (3) and mitoxantrone (10) are anthraqurnone derivatives which possess potentcytotoxic activity against a variety of cancers in both animal and clinical studies. Ametantrone (3) wasprepared by reacting leucoquinizarin (1) with 2- (2-aminoethylamino) ethanol, followed by air oxidation.The corresponding leuco-compound, 2,3-dihydro-1,4,5,8-tetrahydroxy-9,10-anthracenedione. (7), for thesynthesis of mitoxantrone was not available. A synthetic route starting from chrysazin (4) wasthus developed. Procedures were started by nitration of chrysazin (4), followed by reduction of the nitro-product (5) to give 1,8-dihydroxy-4,5-diamrnoanthraquinone (6), followed by reductive hydrolysis toyield the leuco-1,4,5,8-tetrahydroxyanthraquinone (7). Then, by using the same procedures and reactionconditions as in the synthesis of ametantrone, mitoxantrone could be prepared with a total yield of 32%.High-resolution NMR spectra of both anticancer anthraquinones were determined, and each spectrum wasprecisely assigned. The structure of a naphthoquinoxaline compound, which appeared either as a byproduct during synthesis or as a degradant of nutoxantrone in aqueous solution, was elucidated. of mitoxantrone in mice was determined to be 57 mg/Kg from a safety test carried out by intravenousadministration. Antileukemic activity of the synthesized mitoxantrone was conducted and proved to beequally potent by comparing with a commercial product.
- 中文關鍵字: mitoxantrone; ametantrone; anticancer; anthraquinone; safety test
- 英文關鍵字: --