含有香豆素的石膽酸類似物作為唾液酸轉移?抑制劑的合成與初步活性測試; A Series of Lithocholic Acid Analogs with Coumarin Moieties as Sialyltransferase Inhibitors: Synthesis and Preliminary Bioactivity Studies

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题名:	含有香豆素的石膽酸類似物作為唾液酸轉移?抑制劑的合成與初步活性測試;A Series of Lithocholic Acid Analogs with Coumarin Moieties as Sialyltransferase Inhibitors: Synthesis and Preliminary Bioactivity Studies
作者:	呂柏葦;Lu,Po-wei
贡献者:	化學學系
关键词:	唾液酸;唾液酸轉移?;香豆素;sialic acid;Sialyltransferase;Coumarin
日期:	2013-08-26
上传时间:	2013-10-08 15:07:57 (UTC+8)
出版者:	國立中央大學
摘要:	近年來，癌症的轉移往往伴隨唾液酸轉移?的異常表現，因此發展唾液酸轉移?的抑制劑，並測試其抑制活性，了解化合物結構與抑制能力的關係，期望能以抑制唾液酸轉移?為分子標靶來達到抗癌症轉移的效果。以Lith-O-Asp 為主結構，並透過DMMTM BF4 耦合試劑和SOCl2 醯氯化合成醯胺鍵連接一系列的香豆素衍生物，分別透過細胞傷口癒合分析及唾液酸轉移 ?抑制實驗來探討香豆素衍生物上的取代基對於生物活性的影響。透過生物實驗可以發現KE-49、KE-50、KE-89 及KE-126 有較明顯的抑制能力，代表香豆素上的羥基有助於增進抑制活性，其中又以C7 號位的羥基取代最為明顯，另外在 C8 號位增加一個甲基取代也有助於活性的提升。 Recently, aberrant sialylation is found in cancer metastasis frequently. Empolying the strategy of the relationships between structure and activity , we use sialyltrasdferase as the molecular target to develop its inhibitors in order to attenuate cancer metastasis. Preparation of Lith-O-Asp-coumarin derivatives was successfully accomplished through the coupling reaction between Lith-O-Asp and coumarin moieties using DMMTM BF4 (4-(4,6-dimethoxy-(1,3,5)triazin-2-yl)-4-methyl-morpholinium tetrafluoroborate) or SOCl2 as the reagents. Extensive SAR studies were performed using different substituted-coumarin analogs under the wound healing and sialyltransferase inhibitor assays. Among the Lith-O-Asp-coumarin derivatives, the hydroxyl-substituent analogs at C-7 position were observed to have the hightest biological activity. It is also noteworthy that the methyl-substituent analogs at C-8 position also display significantly increased biological activity toward both assays.
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