苯并咪唑衍生物作為間變性淋巴瘤激酶/組蛋白去乙醯酶雙重抑製劑之設計與合成

Design and Synthesis of Benzimidazole Derivatives as Anaplastic Lymphoma Kinase / Histone Deacetylase Dual Inhibitors

林怡君(I-Chun Lin)

指導教授 ： 陳基旺

國立臺灣大學/醫學院/藥學研究所/碩士(2017年)

https://doi.org/10.6342/NTU201703229

摘要

近年來認為對於像癌症這類的多基因疾病，使用多標靶治療會優於單一標靶治療，並且單一藥物可以避免組合治療所產生的限制。本研究的目的即是設計並合成ALK / HDAC雙重抑制劑作為多標靶抗癌藥物。
目標化合物的設計理念為結合兩個不同的藥效基團使之具有雙重活性。化合物21被選作先導化合物，以不同的連接鏈連接鋅結合基團做結構活性探討。結果顯示2-醯胺基苯并咪唑衍生物皆有ALK抑制活性。其中化合物52具有良好的ALK和HDAC6抑制活性，可作為ALK / HDAC雙重抑制劑。另外，將2-醯胺基苯并咪唑換成苯并咪唑會失去ALK抑制活性，卻有較佳的HDAC抑制活性，此核心結構可做為HDAC抑制劑發展。然而此系列之化合物溶解度差。細胞試驗中的活性弱可能是通透性與類藥性差所導致。在第二章，利用苯并咪唑核心結構接上嗎福林側鏈以提高水溶性。雖然這一類化合物之溶解度有所改善，卻還是低於0.01 mg/mL，並在細胞毒殺試驗中依舊無活性。化合物在酵素活性與細胞毒殺效果上的結果並無關聯性，這可能是因為類藥性差所致。這些問題在未來皆需要再被釐清。

關鍵字

抗癌藥物 ； 雙效抑制劑 ； 苯並咪唑 ； 水溶性 ； 類藥性

並列摘要

It is generally accepted that multi-therapeutics may be better than mono-therapies for multigenic diseases such as cancer; besides, single agent can avoid the limitation caused by a combination regimen. The aim of this study is to design and to synthesize ALK / HDAC dual inhibitors as novel multi-targeted anti-cancer agents.
The concept of compound design is merging two diverse pharmacophores to obtain one molecule with dual activities. Compound 21 is selected as a lead coupled to different linker connecting with zine binding group for the structure activity relationship (SAR) study. The results show that the 2-acyliminobenzimidazole derivatives all have ALK inhibition. Compound 52 illustrating both ALK and selective HDAC6 inhibitory activity may be considered as ALK / HDAC dual inhibitor. On the other hand, compounds replacing 2-acyliminobenzimidazole with 2-substituted benzimidazole lose ALK inhibition, but with better HDAC inhibition. This core structure can be used to developed as the HDAC inhibitors. However, this series of compounds have poor water solubility. The weak activity in cellular assays may be due to poor permeability and drug-like properties. In Chapter 2, benzimidazole core structure is coupled to morpholine side chain in order to improve the water solubility. Although the solubility has been improved, it is still lower than 0.01mg/mL. The cytotoxic assays did not show activity. There is no correlation between enzymatic inhibitory activity and antiproliferation. This is probably due to the poor drug-like properties. This issue still need to be further clarified.

並列關鍵字

Anti-cancer agents ； Dual inhibitors ； Benzimidazole ； Water solubility ； Drug-like properties

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