設計與合成苯並咪唑衍生物作為抗癌試劑

Design and synthesis of benzimidazole derivatives as anticancer agents

柯弼文(Ko, Pi Wen)

指導教授 ： 孫毓璋 ； 許銘華

國立清華大學/原子科學院/生醫工程與環境科學系/碩士(2015年)

https://doi.org/10.6843/NTHU.2015.00272

摘要

在本論文中，我們合成二十四個苯並咪唑衍生物來探討其在A549(人類肺癌細胞)、MCF-7(人類乳腺癌細胞)、HEP-G2(人類肝癌細胞)及OVCAR-3(人類卵巢癌細胞)的細胞毒殺性。在OVCAR-3的實驗中，其中有十一個化合物IC50介於10.34 - 14.88 μM低於化療藥物順鉑(cisplatin)的IC50值(16.04 μM)。大部分的受測化合物具有當抗癌藥物的潛力在對抗A549, MCF-7 及 OVCAR-3 等癌細胞，然而化合物7a、8a及9a最具有潛力。化合物7a在對抗這四種癌細胞的IC50值與順鉑接近或是更低。此外，使用流式細胞儀進行OVCAR-3癌細胞週期實驗，結果顯示化合物8a及9a會在G2/M的細胞週期造成阻礙，推斷可能是毒殺細胞的原因之一。總而言之，這新的系列氮取代苯並咪唑衍生物可作為往後抗癌藥物的結構原型。

關鍵字

苯並咪唑 ； 抗癌

並列摘要

In an effort to establish new candidates with improved anticancer activity, we report here the synthesis of various series of N- substituted benzimidazole derivatives. The cytotoxicity of these compounds were determined using four cancer cell lines, A549 (human lung carcinoma cell line), MCF-7 (human breast adenocarcinoma cell line), HEP-G2 (human hepatocellular carcinoma cell line) and OVCAR-3 (human ovarian carcinoma cell line). Among the tested derivatives, there were 11 compounds (6c, 6d, 7a, 7b, 7c, 8a, 8c, 8d, 9a, 9b, 9c) possessing between 10.34 and 14.88 μM were lower than 16.04 μM (the IC50 value of cisplatin) for OVCAR-3 cells. Although most compounds examined were quite effective on A549, MCF-7 and OVCAR-3 cells, the compounds (E)-3-phenyl-1-(1-(2-(piperidin-1-yl)ethyl)-1H-benzo[d]
imidazol-2-yl)prop-2-en-1-one (7a), (E)-3-phenyl-1-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-
benzo[d]imidazol-2-yl)prop-2-en-1-one (8a) and (E)-1-(1-(3-morpholinopropyl)-1H-
benzo[d]imidazol-2-yl)-3-phenylprop-2-en-1-one (9a) emerged as the most active compounds of this series. In particular, the compound 9a possessing great IC50 values on A549, MCF-7, HEP-G2 and OVCAR-3 cells showed in vitro cytotoxicity similar or even better than cisplatin. Additionally, compound 7a and 8a showed effective cytotoxicity on OVCAR-3 cells and arrested the cells at G2/M at a similar concentration of MTT experiment. Therefore, the result of flow cytometry showed that compound 7a and 8a have abilities to arrest cell cycle progression. In summary, we conclude that the novel series of N- substituted benzimidazole derivatives can serve as a prototype molecule for further development of a new class of anti-cancer agents.

並列關鍵字

benzimidazole ； OVCAR-3 ； anti-cancer

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