合成雙重保護之前驅藥物藉級聯光解與蛋白酶解達可控釋放

Synthesis of Controllable Double Capped Prodrug via Cascade Photolysis and Proteolysis

洪鉦翔(Cheng-Hsiang Hung)

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/NTU202000656

摘要

前驅藥物(prodrug)是本身沒有藥物活性或活性很低的分子，在體內透過酵素代謝、化學反應等，轉化為具活性的原型藥物。前驅藥物始於偶然發現，而今已轉變為針對原型藥展開各種合理化設計。設計目的是為了針對藥理學上具有潛力的化合物去改善其物理化學特性(溶解性、化學穩定性和感官特性)、藥效(毒性和治療程度)或藥物代謝動力學(吸收途徑如口服或靜脈注射、系統間代謝及時間特徵，活性劑的組織或器官選擇性遞送能力)。於本研究中，目標是開發一種雙重保護之前驅藥物的新策略。在前驅藥物的結構中，身為核心的胺被設計由兩種保護基同時保護──可被光裂解的基團(PPG)和可被組織蛋白酶B(CTSB, Cathepsin B)作為受質的雙肽。組織蛋白酶B在多種惡性腫瘤的發展進程中，扮演重要角色和有較高的表達量。透過此策略設計的阿黴素(DOX, Doxorubicin)之前驅藥物，惟有依序被光解及蛋白酶解，才能釋放原型藥物，以期改善此抗癌藥物廣為人知的藥物副作用。由模型試驗的釋放結果中，顯示此雙重保護之前驅藥物策略為可行，亦即可透過光及酵素達到釋放的調控。基於此新穎策略的開展，需要更進一步的研究來驗證和拓展此策略到不同的官能基團與調控目標化合物之釋放。

關鍵字

前驅藥物 ； 藥物釋放 ； 光解 ； 蛋白?解

並列摘要

Prodrugs are molecules with little or no pharmacological activity that are converted to the active parent drug in vivo by enzymatic or chemical reactions or by a combination of the two. Prodrugs have evolved from being serendipitously discovered or used as a salvage effort to being intentionally designed. They are designed in order to improve the physicochemical, biopharmaceutical or pharmacokinetic properties of pharmacologi¬cally potent compounds. In this work, we take our aim at developing a novel strategy of the double-capped prodrug. The free amines of the core in our prodrug are designed to blocked with a photoremovable protecting group (PPG) and a dipeptide which is sensitive against cathepsin B (CTSB), which is highly upregulated in malignant tumors and premalignant lesions. The prodrug of doxorubicin is only released while it is sequentially cleaved by photolysis and proteolysis. Thus, the notorious side effect of doxorubicin (DOX) can be improved. The result of the releasing assay suggest that our double prodrug strategy is practical. Further studies are needed to validate and expand the scope of this novel strategy to different functional groups and controlled release.

並列關鍵字

prodrug ； double-capped prodrug ； drug release ； photolysis ； proteolysis

參考文獻

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