設計開發環氧酮前驅物之共價前驅藥物

Design novel prodrugs of covalent inhibitors with controllable epoxyketone precursors

柯明甫(Ming-Fu Ko)

指導教授 ： 王宗興

國立臺灣大學/理學院/化學研究所/碩士(2020年)

https://doi.org/10.6342/NTU202000416

摘要

共價抑制劑 (Covalent Inhibitors, CI) 擁有高藥效、較低的劑量、作用持久的優勢。但脫靶效應(off-target effect) 的產生使得CI的發展受阻。最近，大量帶有環氧酮 (epoxyketone) 彈頭的標靶共價抑制劑（Targeted Covalent Inhibitors, TCI）表現出有效的抗癌特性。前驅藥物(prodrug)的策略能專一性地辨識藥物的作用位點，並有效地調控共價抑制藥物的釋放與活性，能帶來降低副作用的優勢。因此，我們將TCI和前藥的概念融合，利用兩者分別的優勢開發出有效的策略來設計發展的具環氧酮前驅物的前藥。
由於環氧酮包含兩個活性親電基團，一個是環氧化物和一個羰基。在本文中，我們展示了兩種調控策略：1. 調控環氧化物的生成2.羰基封端的生成。我們假設並驗證了溴代醇能在生理環境下生成環氧化物，接著用可光觸發的三甲基鎖關環基團保護住溴代醇，並利用鄰硝基苯基乙烯構建可光觸發的二醇酯保護住羰基。兩種策略均顯示出前要保護策略具有足夠的穩定性和光觸發至釋放環氧酮的優勢。我們還發現有趣的是，鹵代醇的結構異構，α位上甲基的存在也影響了彈頭的形成。此外，我們的策略展示了有修飾各種含環氧酮的TCI的潛力。

關鍵字

前驅藥物 ； 環氧酮 ； 共價抑制劑 ； 脫靶效應 ； 彈頭

並列摘要

Covalent inhibition has been viewed as a promising strategy in the pharmaceutical industry for its high biochemical efficiency and lower dosage. However, off-target effects remain troublesome. Recently, plenty of Targeted covalent Inhibitors (TCI) with epoxyketone warheads showed effective anticancer characteristics. In addition, prodrug are often designed to improve bioavailability and reduce adverse effects of inhibitors. Therefore we amalgamated the concepts of TCI and prodrugs in order to develop effective strategies for modification of potent epoxyketone warheads.
Due to epoxyketone contains two electrophilic moieties that are active against intrinsic nucleophiles , an epoxide and a carbonyl group. Herein, we demonstrated two capping strategies 1. the capping of the epoxide 2. capping of the carbonyl group. We investigated through different cappings and immolative linker and came out with capping the bromohydrins with photo-triggerable TML groups and capping the carbonyl group by utilizing o-nitrophenylethylene for contruction of photo-triggerable diololanes. Both strategies shown sufficient stability and temporal control of parent epoxyketones. We also found it interesting that the constitution isomerism of halohydrin, presence of a methyl group on the α-position also influences the warhead formation. Furthermore, our strategy shows potential to modify various epoxyketone containing TCIs

並列關鍵字

prodrug ； epoxyketone ； covalent inhibitor ； off-target effect ； warhead

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