Src蛋白抑制劑：AC93253衍生物活性評估及吲哚衍生物合成

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题名:	Src蛋白抑制劑：AC93253衍生物活性評估及吲哚衍生物合成
其它题名:	Src Protein Inhibitors：Biological Evaluation of AC93253 Derivatives and the Synthesis of Indole Analogs
作者:	林長慶 LIN, CHANG-CHING
贡献者:	吳雨珊 WU, YU-SHAN 化學系
关键词:	Src蛋白抑制劑 Src Protein Inhibitors
日期:	2017
上传时间:	2018-03-30T01:07:16Z (UTC)
摘要:	肺癌是所有癌症中死亡率最高的。Src蛋白是一個酪胺酸激酶，在肺癌細胞中Src蛋白較一般細胞活躍，會導致癌細胞的增生、移動和血管新生，因此Src可以作為肺癌治療的標靶。先前研究中利用電腦模擬輔助藥物設計程式(CADD)和生物活性實驗的方式，得到對Src蛋白具有抑制性的兩種化合物AC93253及WY1339。本研究首先利用西方墨點法和細胞存活分析來探討一系列AC93253衍生物，其中衍生物A10有最佳的Src抑制能力和肺癌細胞毒殺效果。另外在低濃度下，A10對肺癌細胞的細胞功能皆有顯著的抑制能力，包括癌細胞的增生、移動、轉移、及細胞群落形成的能力。本研究也以WY1339為先導化合物，設計合成出一系列以吲哚為主體，不同長度、不同取代基的衍生物。根據生物活性的結果，WY1339結構中吲哚6號位置的取代基消失會降低抑制肺癌細胞的效果。將吲哚上6號位置的苯環取代基更改為苄基時會降低對肺癌細胞株A549的抑制能力。而所有衍生物中，L43對A549具有較佳的毒殺效果(IC50為39.91 μM)。 Lung cancer is the leading cause of cancer death. In lung cancer cells, Src protein is more active than in normal cells as it induces cell proliferation, migration and angiogenesis. It is thus a good target for the development of lung cancer treatment. In previous research, we have identified two compounds, AC93253 and WY1339 by CADD as Src inhibitors and their inhibitory activities were verified by in vitro studies. In this study, western blot and cell survival analysis were performed to a series of AC93253 derivatives. Derivative A10 was found to exhibit most Src inhibitory activity and cytotoxicity against lung cancer cells. At low concentrations, A10 significantly inhibited lung cancer cell functions such as proliferation, migration, invasion, and colony formation. We have taken WY1339 as lead compound and further designed a series of substituted indole derivative. MTT assay revealed that when there was no substituents or replacement of phenyl by benzyl group at 6th position of indole, the cytotoxicity against lung cancer cells decreased drastically. Within all the derivative synthesized, L43 exhibited better activity against A549 lung cancer cell line with IC50 of 39.91 μM.
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