設計與合成比咯苯偶氮駢混成試劑與雙體之抗癌烷化試劑

Design and Synthesis of Pyrrolo[2,1-c][1,4]benzodiazepine Hybrids agent and Dimers as Antitumor Alkylation Agents

陳建宇(Chung-Yu Chen)

指導教授 ： 王志鉦

高雄醫學大學/生命科學院/醫藥暨應用化學研究所/碩士(2009年)

摘要

比咯苯偶氮駢 ( pyrrolo [2,1-c][1,4] benzodiazpines 簡稱:PBDs)，是一種由鏈黴菌所分離出來的抗癌試劑，PBDs可以和去氧核醣核酸(DNA)進行一個不可逆的烷化反應，在DNA的次溝槽以共價鍵結的方式形成一個鳥糞嘌呤複合物，阻斷微生物體內分子複製增生的機轉，來達到抗癌的效果。

在本論文中，我們將分別討論比咯苯偶氮駢單體與雙體合成的設計與合成。單體是於A環C-8的位置上以不同碳數的長碳鏈與Gallic Acid的衍生物進行鏈結，形成PBD-Gallic Acid的混成試劑，雙體則是在A環C-8位置上以ρ-xylylene bromide進行雙體連接，以期可以得到更好的抗癌活性。

關鍵字

混成試劑 ； 抗癌藥物 ； 比咯苯偶氮駢

並列摘要

Pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) are natural products extracted from many kinds of Streptomyces, and exhibited high bioactivities of anti-biotics and anti-tumors in past reports.The PBDs can be interact with DNA in high sequence – selective active, because PBDs can form a covalent bond with DNA guanine in the minor groove. This mechanism of PBDs-DNA adduct inhibit DNA replication and transcription, which interfere with the tumor cell proliferation. This adduct formation is thought to lead to the observed biological activity.

In this thesis, we designed and syntheized a series of Gallic Acid derivatives linked with PBDs as anti-tumor agents. As well as synthesized a PBDs dimmer which cross-linking with ρ-xylylene bromide at head to head(C-8/A). Four of them has been synthesized and sent to NCI for screening test. This hybrid agent compounds had great biological activity result.

並列關鍵字

hybrid agent ； anti-cancer ； PBD ； dimer ； gallic acid

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