吲哚類抗癌化合物之合成和結構與活性關係(SAR)的研究

Synthesis and Structure-Activity Relationship of Indole Compounds as Anticancer Agents

陳傑文(Chieh-Wen Chen)

指導教授 ： 廖俊臣 ； 謝興邦

國立清華大學/理學院/化學系/碩士(2009年)

摘要

本論文的主旨在於研究一系列以吲哚 (indole) 為主架構的抗癌藥物之設計與合成，並進一步的探討這系列化合物的結構與抗癌生物活性之相關 (structure -activity relationship，簡稱為 SAR)。

在抗癌機制上的主要研究方向為研發抗有絲分裂試劑，以阻礙癌細胞之細胞週期，進而達到抗癌之效果。而在研究過程中，可分成兩階段 : 第一階段是以微管作為抗癌標靶之藥物設計；第二階段則是以極光激酶 A (Aurora kinase A) 作為抗癌標靶之藥物設計。

在這系列的吲哚化合物中，以帶有 3-甲基吡唑 (3-methylpyrazole) 的化合物擁有對於極光激酶 A 的抑制活性，抑制效果最高可達 77%，而化合物 9c 更對於人類結腸癌細胞株 HCT116 (human colon cancer - 116 cell line) 顯現出明顯的抗癌生物活性 (IC50 = 2.6 μM) ，並以此化合物作為先導化合物 (lead compound) 做結構與抗癌生物活性之相關之探討。

關鍵字

吲哚 ； 抗癌藥物

並列摘要

This dissertation is focused on the design and synthesis of the indole system compounds as anticancer drugs, and a study on their structure-activity relationship (SAR) outlined as follows.
For the anticancer drug design we intend to make antimitotic agents to disrupt the cancer cell’s cell cycle. In our study, there are two stages. At the initial stage, we use microtubules as the anticancer target to design the drug. Then, we change the target to the Aurora kinase A.
In this series indole compound that we prepared, we found that the compound which has the 3-methyl pyrazole as the heterocyclic part can be the Aurora kinase A inhibitor, and the highest case can inhibit around 77% Aurora kinase A. The compound 9c has the anticancer bioactivity of 2.6 μM (IC50) against the HCT116 (human colon cancer - 116 cell line). Furthermore we use this compound as the lead compound to make the SAR (structure -activity relationship) for further study and optimization.

並列關鍵字

indole ； anticancer drugs

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