部分氟取代石膽酸類似物作為唾液酸轉移酶抑制劑的合成與初步生物活性之探討

Partially Fluorinated Lithocholic Acid Analogs as Sialyltransferase Inhibitors: Synthesis and Preliminary Bioactivity Studies

郭于綸(Yu-Lun Kuo)

指導教授 ： 朱延和 ； 李文山

國立中正大學/理學院/化學暨生物化學系/碩士(2013年)

摘要

根據許多文獻報導得知唾液酸轉移酶的異常表現量與許多癌症有重要的關連性，因此能發展出具良好活性的唾液酸轉移酶抑制劑，進而調控唾液酸轉移酶的表現途徑，是我們實驗室致力合成的宗旨與目標。
本文所合成之化合物主要是將石膽酸主體作改變，利用石膽酸、脫氧石膽酸、鵝脫氧膽酸、豬去氧膽酸、熊去氧膽酸及膽酸作為主體，並將其氫原子或羥基基團換成單一的氟或是雙氟，分別在A、B、C ring上，以各種不同排列組合的方式在C3、C7及C12位置上，得到不同數量與不同位置的氟取代石膽酸衍生物。
接著將所合成之化合物作生物活性測試，以石膽酸的活性結果為基準，利用MDA-MB-231 乳癌細胞進行細胞傷口癒合測試，發現化合物YL-38與YL-44具有抗轉移的潛力，並針對α2,3-(O)-唾液酸轉移酶抑制活性測試結果得知，化合物YL-34、YL-72與YL-80具有不錯的抑制效果，可作為唾液酸轉移酶抑制劑的前驅化合物。

關鍵字

唾液酸轉移酶抑制劑 ； 唾液酸轉移酶 ； 唾液酸 ； 氟取代化合物

並列摘要

According to many reports, abnormal expression of the sialyltransferase has been found to actually connect with many cancers. Therefore,purposes and objectives of this study are making effort to develop effective sialyltransferase inhibitors and regulate the level of sialyltransferase expression.
In the thesis, we initially synthesized potential sialyltransferase inhibitors of the fluorine-substituted lithocholic acid derivatives. Then we use lithocholic, deoxycholic acid, chenodeoxycholic acid, ursodeoxycholic acid hyodeoxycholic acid and cholic acid as their parent skeleton, and take a place of a hydrogen atom or hydroxyl groups to single fluorine or two fluorines. Employing the strategy of permutation and combination, twelve fluorine-substituted lithocholic acid derivatives at the C3, C7 and C12 position in the A, B, C ring of the skeleton were synthesized respectively.
We next took all the flourine-substituted analogs to do the bioactivity test of wound healing and α2 ,3-sialyltransferase inhibition test. Interestingly, we found that compounds YL-38, YL-44 possess potent anti-metastasis ability and compounds YL-34, YL-72, and YL-80 could be identified as protential α2 ,3-sialyltransferase inhibitors in comparison with the parent compound, lithocholic acid.

並列關鍵字

sialyltransferase inhibitors ； sialyltransferase ； sialic acid ； fluorinated compound

參考文獻

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