合成1-Aroylindoles/indolines為抗癌試劑

Synthesis of 1-Aroylindoles/indolines as Anticancer Agents

吳家賢(Chia-Hsien Wu)

指導教授 ： 林美香

共同指導教授 ： 劉景平(Jing-Ping Liou)

臺北醫學大學/藥學院/藥學系(碩博士班)/碩士(2014年)

摘要

1960年代，Ritossa發現了“heat-shock”反應，並了解到chaperone的存在，也就是所謂的熱休克蛋白(Heat-shock proteins)。目前研究發現，癌症細胞中熱休克蛋白會異常地活化，以及維持癌細胞的生長。在熱休克異常活化的癌症中，發現Hsp90在腫瘤細胞中過度表現並且與黑色素瘤、乳腺癌、胃腸道基質腫瘤、非小細胞肺癌有密切的關聯。因此，Hsp90在抗癌發展中是一個重要的標靶藥物。

目前至少有二十個Hsp90抑制劑進入臨床試驗。目前進入臨床試驗的Hsp90 抑制劑有17-AAG (Tanespimycin)，目前進入臨床三期，用於治療多發性骨髓瘤(Multiplemyeloma)；BIIB021目前完成臨床二期，用於治療胃腸道基質瘤(Gastrointestinal Stromal Tumors)。

本實驗室參考了目前在臨床二期的Hsp90 inhibition AT13387，發現 2,4-dihydroxybenzamide是具有抑制活性的良好基團。因此，在結構設計上保留此基團，同時修飾isoindoline ring改變成1-aroylindole與1-aroylindoline，並在indole/indoline的4號位與5號位接上各種官能基，進而探討抑制活性與結構的相關性。由抗增殖活性數據顯示，發現在4號位接上-NH2的indoline ring化合物85具有較好的抗增殖活性，對於人類肺腺癌上皮A549細胞的GI50值為0.48 μM。

關鍵字

熱休克蛋白90

並列摘要

In the 1960s, Ritossa discovered the "heat-shock" response, and found the existence the chaperone which is also known as heat shock protein. Current study found that heat shock is overexpressed in cancer cells; In addition, it maintains the growth of cancer cells. Hsp90 is the most overexpressed among those heat shock proteins, and is highly associated with melanoma, breast cancer, gastrointestinal stromal tumors, and non-small cell lung cancer. Therefore, it becomes a significant target for developing anticancer agents.

Up to date there are more than 20 Hsp90 inhibitors undergoing the clinical trials. For example, 17-AAG (Tanespimycin) is currently undergoing phase III clinical trials, and is used in the treatment of multiple myeloma. BIIB021 is used to treat gastrointestinal stromal tumor, and has completed the phase II clinical trials.

AT13387, an Hsp90 inhibitor in the phase II clinical trial, was selected as the starting point of this thesis. Literature survey indicated that 2,4-dihydroxybenzamide group is an important moiety contributing biological activity. Hence, we retained the core, replaced the isoindoline ring with 1-aroylindole or 1-aroylindoline, and the substitution effects at C-4 and C-5 positions on biological activity is discussed as well with the expection to afford more active compounds. Compound 85 at with a C-4 -NH2 inhibited A549 cancer cell line with GI50 values of 0.48 μM.

並列關鍵字

Hsp90

參考文獻

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