石膽酸C4含氟唾液酸轉移酶抑制劑和苯並惡嗪酮相關的螢光探針之合成及生物研究

Synthesis and biology of lithocholic acid C4 fluorine-containing sialyltransferase inhitors and benzoxazinone-related fluorescent probes.

劉明鑫(Ming-Xin Liu)

指導教授 ： 李文山 ； 侯敦仁

國立中央大學/理學院/化學系/碩士(2015年)

摘要

第一部份
根據研究指出唾液酸轉移酶的異常表現量與許多癌症有關聯。因此能發展出具良好活性的唾液酸轉移酶抑制劑，進而調控唾液酸的表現途徑，是我們實驗室努力的目標。本文所合成的化合物是以石膽酸為主結構，利用具有高效率與選擇性的Selectfluor試劑在C4位置引入一個氟原子做修飾，並進一步合成出Lith-O-Asp-NBD之氟取代衍生物做為有效的抗癌化合物。分別透過MTT assay及Wound healing assay實驗來探討氟取代石膽酸類似物對於生物活性的影響。透過生物實驗發現化合物JO-5b、JO-13a、JO-13b具有較好的抑制效果。
第二部分
螢光標記法具有高靈敏度、選擇性好等優點，目前應用相當廣泛。近年來新型的分子顯影劑之臨床轉譯與發展透過早期病變檢測、分子標靶治療、治療監測以及開發新的抗癌藥物能夠明顯改善乳癌患者的癌症轉移。本文所合成的化合物是以benzoxazinone為主體，藉由修飾其官能基來探討分子探針之結構與量子產率之間的關係。透過光學性質分析發現JO-35的量子產率最高 (Φ = 0.39)，其結構上的胺基會與環上的氧原子形成分子內氫鍵，若是替換成其他官能基會使分子探針失去螢光的特性。

關鍵字

唾液酸 ； 螢光標記

並列摘要

PartI.
According to many researches, 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, the main structure of our compounds are lithocholic acid. We used high efficient and selective reagent─Selectfluor to add a fluorine atom at the C4 position as modification, and we synthesized fluorinated compound of Lith-O-Asp-NBD as effective anti-cancer compound further.Through MTT assay and Wound healing assay experiment to discuss fluorinated compound’s influence on biologically activity. Interestingly, We found that compounds JO-5b, JO-13a, JO-13b possess potent anti-metastasis ability.
PartII.
Fluorescent labeling has the advantage of high sensitivity and good selectivity for the use in a wide range of applications. In recent years, novel molecular imaging agents were developed for the use of clinical translation through early lesion detection, molecular targeted therapy, therapeutic monitoring, and the development of new anti-cancer drugs. This action significantly improves diagnosis and therapy in patients with breast cancer metastasis. In this thesis, the main structure of our compounds is benzoxazinone. We modified its functional group to explore the relationship between structure and fluorescent quantum yield of molecular probes. Through analysis of the optical property, we found that Jo-35 has the highest quantum yield (Φ = 0.39) compared to that of others. Intramolecular hydrogen bond was confirmed in the skeleton between oxygen atom and amino group of the benzene ring. Molecular probes drop the fluorescent property if the intramolecular hydrogen bond is absent due to replacement of the amino group by other atom and/or moiety.

參考文獻

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