beta-Lapachone 衍生物的化學合成及生物活性評估

Synthesis and Biological Evaluation of beta-Lapachone Derivatives.

彭馨誼(Shin-I Peng)

指導教授 ： 鄭智美

高雄醫學大學/生命科學院/醫藥暨應用化學研究所/碩士(2011年)

https://doi.org/10.6832/KMU.2011.00043

摘要

??-lapachone是由黃鐘花醌(lapachol)經簡單的化學合成而製得的藥物，具有複雜的藥理活性，例如: 抗病毒、抗寄生蟲、抗惡性腫瘤以及抗發炎等。本實驗室??-lapachone經結構上的修飾，合成一系列的衍生物，希望可以改善其劇烈細胞毒的缺點，但同時保留其優越的抗發炎生物活性。據先前研究顯示，在lipopolysaccharide (LPS)誘發發炎反應的實驗中，??-lapachone可以經由調控nuclear factor- kappa B (NF-?羠)和mitogen-activated protein kinases (MAPK)訊息路徑去抑制nitric oxide (NO)和prostaglandin E2 (PGE2)等細胞激素的生成，達到抑制發炎的效果。所以本次的研究主要目的為利用對NO的抑制能力做初步篩選，再將具有抑制活性的化合物繼續做訊息傳遞路徑的深入探討。結果發現，化合物3b會明顯抑制發炎因子NO和TNF-?悁bLPS刺激發炎反應的Raw 264.7小鼠巨噬細胞中。在蛋白質層面，西方點漬法結果顯示化合物3b可以有效抑制iNOS及COX-2之蛋白質表現，而在mRNA層面，PCR結果顯示化合物3b會明顯抑制iNOS的mRNA表現。我們更發現，化合物3b可以抑制由LPS所誘導，一旦此轉錄因子被調控，即可抑制細胞分泌促進發炎之細胞激素。總結以上結果，化合物3b在抗發炎藥物研究領域非常具有潛力，且動物實驗的部分在未來也會做更深入的探討。

關鍵字

黃鐘花醌細胞毒 ； 抗發炎生物活性 ； 促進發炎細胞激素

並列摘要

??-lapachone, a derivative synthesized form lapachol, is a chemotherapeutic agent that exhibits varieties of pharmacological actions, such as, anti-virus, anti-parasitic, anti-cancer and anti-inflammatory. In this study, we synthesized a series of derivatives of ??-lapachone hoping that can decrease toxicity and conserve anti-inflammatory activity. As an anti-inflammatory agent, ??-lapachone can significantly inhibit NO and PGE2 released form LPS-stimulated Raw 264.7 by regulating NF-κB and MAPK pathway. According to the result from NO inhibition activity, we selected one of these derivatives for further investigation. The result indicated that, compound 3b can inhibit NO and TNF-???nreleased in LPS-induced Raw 264.7, and the inhibition of iNOS and COX-2 was also observed. Moreover, compound ?η exhibits anti-inflammatory properties by suppressing the release pro-inflammatory factors by down-regulating NF-κB activation. To conclude, compound 3b is a potential anti-inflammatory agent, and further in vivo investigation is required to exploitation.

並列關鍵字

lapachol ； cytotoxicity ； anti-inflammatory activitiy ； pro-inflammatory factors

參考文獻

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