設計與合成人類胸苷酸激酶之抑制劑

Design and Synthesis of Inhibitors against Human Thymidylate Kinase

黃夢若(Meng-Ruo Huang)

指導教授 ： 方俊民

國立臺灣大學/理學院/化學研究所/碩士(2013年)

https://doi.org/10.6342/NTU.2013.01493

摘要

癌症一直以來是造成國人死亡率居高不下的原因，如何有效對抗癌症因此成為科學家致力研究的方向。目前醫療上廣泛應用的化療藥物小紅莓(doxorubicin)
雖具有良好抑制效果，然而其嚴重的副作用也使得這個藥物的發展受到限制。因此找尋小分子抑制劑來敏化小紅莓對癌症的毒殺能力，進而降低其藥劑量便成為一個開發方向。
根據高通量藥物篩選的結果，YMU1被發現對人類胸苷酸激酶(hTMPK)具有良好的抑制效果，同時在低劑量小紅莓的共同作用下，能選擇性對癌症細胞造成毒殺作用。因此在本篇論文裡，我將YMU1結構中的硫原子置換成其他原子，進而比較其結構與活性的關係。另外，為了改善YMU1的水溶性問題，設計一系列親水性YMU1衍生物也是我們研究的方向。最後，由於二聚體(dimer)結構的化合物具有比YMU1更好的抑制活性，我們合成不同的二聚體衍生物並測試其活性。
由目前合成的30個類似物來看，有7個衍生物已證實具有和YMU1相同，甚至更好的抑制活性。此外，我們也透過這些衍生物歸納出結構與活性之關係，包含硫原子確實在YMU1中扮演重要角色、環上的氫氧基能大幅提升YMU1衍生物之抑制活性，以及二聚體結構普遍具有良好的活性等，希冀能有助於未來的人類胸苷酸激酶抑制劑之開發。

關鍵字

癌症 ； 小紅莓 ； 胸苷酸激酶抑制劑

並列摘要

Cancer has become one of the most fatal diseases in recent 30 years. Anti-cancer drugs such as doxorubicin, which can inhibit the function of type II topoisomerase, have been used extensively. However, doxorubicin treatment causes many side effects including vomit, hair loss, myelosuppression and cardiotoxicity. Searching for new drugs to cure cancer with reduced side effects from doxorubicin has become an important task. After screening a series of compounds, YMU1 was found to inhibit the activity of human thymidylate kinase (hTMPK), which plays an important role in synthesis of DNA. YMU1 could sensitize cancer cells to chemotherapeutic agent such as doxorubicin. The combined use of YMU1 and doxorubicin substantially inhibits tumor growth and reduces the side effect of doxorubicin.
My research aims to modify the structure of YMU1 to find derivatives showing better inhibition against hTMPK. In order to test the importance of sulfur atom in YMU1, the sulfur atom was replaced by other atoms and the inhibitory activities of such derivatives were compared with the sulfur-containing structure. To solve the low solubility of YMU1 in water, I also prepared YMU1 derivatives having high hydrophilicity good for animal experiments. Because dimeric compound has a potential to show better inhibition than YMU1, different cores of dimeric derivatives were synthesized.
Among the above-prepared derivatives, 7 compounds were proved to have either comparable or better inhibition than YMU1. We also made several conclusions for the relationship between structure and activity, including the crucial role of the sulfur atom in the heterocyclic core, the enhanced hTMPK inhibition with a hydroxyl group in the core structure, and better inhibition of the dimeric compounds. This study will be useful for the development of anticancer therapy.

並列關鍵字

Cancer ； Doxorubicin ； Thymidylate Kinase ； Inhibitor

參考文獻

44.Luciferase-coupled TMPK assays were conducted by Zee-Fang Chang’s lab at National Yang Ming University.

53.Molecular docking of compounds 22 and 42 were conducted by Sheh-Yi Sheu’s lab at National Yang Ming University.

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