溴化吳茱萸次鹼衍生物之生物活性探討

Biological activities of synthetic bromo-rutaecarpine derivatives

楊哲雄(Che-Hsiung Yang)

指導教授 ： 林俊茂

臺北醫學大學/醫學院/醫學科學研究所/碩士(2012年)

https://doi.org/10.6831/TMU.2012.00088

摘要

吳茱萸次鹼是由中藥材芸香科落葉灌木植物吳茱萸(Evodia rutoecarpa)熟成的果實中提煉出含有生物活性的成分，之前的研究發現，吳茱萸次鹼可以抑制炎症、降低血壓、抑制血小板聚集和護心血管，此外，近年來在癌症研究的文獻指出，吳茱萸次鹼可藉由抑制癌細胞增殖，使細胞走向凋亡路徑。然而，由於此天然物質的溶解性極差，造成使用上的諸多限制，因此利用有機合成的方法，以其做為模板，期望合成出更具生物活性應用的衍生物。根據本次實驗結果發現，其中的吳茱萸次鹼衍生物二號可以有效的抑制卵巢癌細胞生長，並且非經由過去其他文獻衍生物所標示作用的拓樸異構酶抑制路徑，是以另外途徑造成細胞毒殺效果。而吳茱萸次鹼衍生物四號，則因不具細胞毒性被用來測量其抗發炎反應之機制，在本實驗中，發現其可藉由抑制酸性神經鞘磷脂水解酶達到減少RAW264.7巨噬細胞因LPS誘發導致的神經醯胺含量上升，並可抑制下游NOS2、COX-2等發炎反應蛋白的表現。此為第一個吳茱萸次鹼衍生物被用於抗發炎反應，並且為首次發現吳茱萸類似物質可抑制酸性神經鞘磷脂水解酶之研究。

關鍵字

吳茱萸次鹼 ； 吳茱萸次鹼衍生物 ； 神經醯胺 ； 神經鞘磷脂水解酶

並列摘要

The rutaecarpine is a bioactive ingredient extracted from the ripe fruit of Evodia herbal medicines. Previous studies found that rutaecarpine possesses the activities to inhibit inflammation, lower blood pressure, platelet aggregation and cardiovascular protection. In addition, rutaecarpine also induces cell apoptosis to inhibit cancer propagation. However, low solubility of this natural substance restricts its biological applications. In this study, several synthetic rutaecarpine derivatives were obtained and their biological activities evaluated. The derivativecompound-2shows growth inhibitory effect against the ovarian cancer A2780R2000,a camptothecin-resistant cells. The cell-killing effect does not go through topoisomarase I inhibition that differs from the mechanism of parental rutaecarpine. The rutaecarpine derivative compound-4 showed the most potent on anti-inflammation among the synthetic derivatives. The rutaecarpine derivative compound-4 inhibits acid sphingomyelinase and reduces intracellular ceramide amount in LPS-induced RAW264.7 macrophage. It also inhibits expression of the proinflammatory protein NOS2, COX-2. This is the first disclosure for rutaecarpine derivatives acting on acid sphingomyelinase to contribute to its anti-inflammation effect.

並列關鍵字

rutaecarpine ； rutaecarpine derivative ； ceramide ； sphingomyelinase

參考文獻

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