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    Please use this identifier to cite or link to this item: http://ir.lib.ncu.edu.tw/handle/987654321/6399

    Title: 一、石膽酸衍生物合成: 香豆素、NBD及其它官能基之石膽酸類似物做為有效的抗癌化合物和生物探針 二、合成Malyngamide 1和Isomalyngamide A類似物成為唾液酸轉移?的抑制劑:具鏈長及官能基依賴性之結構活性關係研究 (1);Synthesis of modified lithocholic acids: coumarin, nitro-2,1,3-benzoxadiazole and other functional groups as effective anticancer agen
    Authors: 徐瑞靜;Jui-Ching Hsu
    Contributors: 化學研究所
    Keywords: 唾液酸轉移酶;sialyltransferase;lithocholic acid
    Date: 2008-07-09
    Issue Date: 2009-09-22 10:18:53 (UTC+8)
    Publisher: 國立中央大學圖書館
    Abstract: 第一部分: 石膽酸衍生物合成: 香豆素、NBD及其它官能基之石膽酸類似物做為有效的抗癌化合物和生物探針 唾液酸轉移酶的過度表現是細胞組織的生物過程,在許多生理上和病理上有扮演重要的角色,例如:細胞間的黏附、癌症轉移及感染息息相關,所以本實驗室嘗試去改善由石膽酸為骨架,所衍生的唾液酸轉移酶抑制劑,找到一系列效果更好的抑制劑。其中,首度合成出石膽酸結合香豆素(coumarin)衍生物及一些疏水性基團和NBD (7- Nitro-2,1,3-benzoxadiazole)的新型複合物,找到可穿透細胞膜的化合物5-25,其中還有些對唾液酸轉移酶的抑制效果IC50值已經達到接近nM的等級;在乳癌癌細胞實驗中,以20 μM的濃度也具有微量4~40%的毒殺效果,且化合物25更進一步證明可以有效抑制癌細胞的轉移,將來在癌症治療中可與化療藥物合併或單獨使用,而香豆素衍生物及NBD具有螢光的性質可進一步作為酵素螢光探針,幫助了解唾液酸轉移酶在細胞中的分佈。 本實驗室並進一步發展具有胺基長鏈的NBD石膽酸化合物32和36,期望將來可以結合在奈米粒子上用來抓取細胞中或組織內的唾液酸轉移酶及相關蛋白,可用來研究此類藥物對細胞中各種蛋白的作用,並幫助了解唾液酸轉移酶的作用機制。 第二部分: 合成Malyngamide 1和Isomalyngamide A類似物成為唾液酸轉移酶的抑制劑:具鏈長及官能基依賴性之結構活性關係研究 Malyngamide 1和Isomalyngamide A是海藻中提煉出來的天然物,其對於唾液酸轉移酶的抑制效果大約到66 μM、77 μM的等級;在乳癌癌細胞實驗中,則具有IC50 = 12.7、2.8 μM很好的毒殺效果,所以合成出一系列相關的結構,期望找到其活性作用的藥效基團並做相關結構活性的探討。 Part I: Synthesis of modified lithocholic acids: coumarin, nitro-2,1,3-benzoxadiazole and other functional groups as effective anticancer agents and biological probes. Overexpression of sialyltransferase is a vital biological process, which plays a role in various physiological and pathological events, such as cell-cell adhesion, tumor cell metastasis and invasions. To increase the inhibitory potency of sialyltransferase, we prepared the coumarin, NBD (7-nitro-2,1,3-benzoxadiazole) and other functional derivatives of lithocholic acid based on our previous studies. Some of these compounds, 5-25, represent the first examples of nanomolar range sialyltransferase inhibitors with cell permeability which had been demonstrated by the experiment of wound healing and the detection of fluorescence imaging of cells incubated with coumarin or NBD derivative of lithocholic acid. Except the property of antimetastasis in wound healing assay, compounds 5-25 also slightly displayed inhibition of the proliferation of breast cancer cells with the inhibitory percentages ranging from 4~40% under the compound dose at 20 ?M. To investigate the capability of lithocholic acid derivatives attracting the sialyltransferase proteins in vitro and in vivo, nanoparticle-based sialyltransferase inhibitors, 32-36, were prepared to tackle this problem. Part II: Analogues of Malyngamide 1 and Isomalyngamide A as inhibitors of sialyltransferases: A structure activity relationship study of chain-length and functional dependence. Malyngamide 1 and Isomalyngamide A are natural products from Marine and display the significant cytotoxic activity against breast cancer cells at the low micromolar level (IC50 = 12.7 and 2.8 μM). Meanwhile, one of them also inhibited alpha-2,3-sialyltransferase activity at micromolar concentration (IC50 = 66 μM). To find out the pharmacophore, several substructures of malyngamide 1 were synthesized, and their inhibitory properties of sialyltransferase and cytotoxic activities against breast cancer cells were also studied.
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