二氫吲哚-2-酮與苯並咪唑衍生物作為潛能多靶點抗癌藥物之設計、合成與生物活性評估

Design, Synthesis and Bio-evaluation of Indolin-2-one and Benzimidazole Derivatives as Potential Multi-targeted Anti-cancer Drugs

王康力(Kang-Li Wang)

指導教授 ： 陳基旺

國立臺灣大學/醫學院/藥學研究所/碩士(2013年)

https://doi.org/10.6342/NTU.2013.10232

摘要

本研究的宗旨是設計與合成新一代的多靶點抗癌藥物，以克服單靶點標靶治療已面臨的許多問題。
目標化合物的設計理念為將兩類不同功能的藥效基團合併，使之具有雙重活性。第二章中，以多重受體酪氨酸激酶抑制劑1為先導化合物，首先經由羥醛縮合得到帶有吡咯的二氫吲哚-2-酮主結構，再經由海克（Heck）反應加上帶有酯類官能基的側鍊，最後將酯轉換為帶有異羥肟酸官能基的目標化合物（12、13、19與23）。目標化合物被發現具有受器酪胺酸脢與組蛋白去乙醯酶雙效抑制活性，後續的生物活性評估更顯示其具有與單靶點藥物相當或更好的抗癌細胞活性，證實了這樣的化合物設計是有效的。
第三章以兩個苯並咪唑化合物為先導化合物，化合物35為間變性淋巴瘤激酶抑制劑，36則為組蛋白去乙醯酶抑制劑，設計出結合兩者結構的間變性淋巴瘤激酶與組蛋白去乙醯酶雙效抑制劑。依序由芳香環取代反應、海克反應將兩個側鍊接上硝基苯環，再以鐵還原硝基後與異硫氰酸酯化合物或溴化氰合環形成苯並咪唑主結構，最後將酯轉換為帶有異羥肟酸官能基的目標化合物（52、59、65、69與72）。生物活性評估結果顯示目標化合物不僅可以同時抑制間變性淋巴瘤激酶與組蛋白去乙醯酶，更可以抑制多種造成抗藥性的突變間變性淋巴瘤激酶。其中具有最佳細胞活性的目標化合物59更在動物試驗中展現良好的活性。這系列苯並咪唑衍生物因具有好的生物活性以及克服抗藥性的能力，非常有潛力繼續發展為抗癌藥物。

關鍵字

抗癌藥物 ； 雙效抑制劑 ； 二氫吲哚-2-酮 ； 苯並咪唑

並列摘要

The aim of this study is design and synthesis novel multi-targeted anti-cancer agents to overcome the problems in single-targeted therapy.
The concept of compound design is merging two diverse pharmacophores to obtain one molecule with dual activities. Multi-RTK inhibitor 1 was the lead compound in Chapter 2. The core structure of pyrrole-indolin-2-one was obtained through aldol condensation, followed by being coupled with the side chain containing an ester through Heck reaction. Finally, the ester was transformed to hydroxamic acid to give target compounds (12, 13, 19 and 23). The target compounds were found to possess RTK/HDAC dual inhibitory activities. Moreover, they have comparable or better cellular activities than single-targeted drugs, proving the concept of design.
In Chapter 3, two benzimidazole compounds were taken as leads, compound 35 is an ALK inhibitor and 36 is a HDAC inhibitor. Following the sequence of aromatic substitution and Heck reaction, the side chains were added onto the nitrobenzene. After reduction of the nitro group, cyclization was carried out with isothiocyanates or cyanogen bromide to give benzimidazole core structures. The hydroxamic acid was then transformed from the ester to yield target compounds (52, 59, 65, 69, 72 and 77). The results suggest they could inhibit not only ALK and HDAC simultaneously, but also ALK mutants, which are key factors of resistance. Target compound 59, with most potent cellular activities, also demonstrated great potency in animal models. With strong activities and abilities to overcome the resistance, the benzimidazole derivatives are promising for anti-cancer drug development.

並列關鍵字

Anti-cancer drugs ； Dual inhibitors ； Indolin-2-one ； Benzimidazole

參考文獻

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