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  • 學位論文

合成6-6雜環類緣物作為新穎組蛋白去乙醯酶抑制劑的研究

Synthesis of [6, 6]-Heterocycles Analogs as A Novel Class of Potent Histone Deacetylase Inhibitors

指導教授 : 劉景平

摘要


組蛋白去乙醯酶 (histone deacetylase, HDAC)與癌細胞生長非常相關,不止對於癌症也可對其他疾病作為治療標靶,且美國FDA (Food and Drug Administration)於2006年通過第一個組蛋白去乙醯酶抑制劑 (histone deacetylase inhibitor, HDACi),即SAHA (Vorinostat, Zolinza○R),用於治療皮膚T細胞淋巴癌 (cutaneous T-cell lymphoma, CTCL),並緊接著在2009年年底通過第二個HDACi,同樣是用於治療CTCL的FK228 (Romidepsin, Istodax○R)。現今尚有許多HDACi正在進行臨床實驗,此類藥物也因而成為了研發重點的抗癌藥物之一。 HDACi大多數是從天然物中萃取純化而得或是由化學合成取得。基本上,HDACi依據結構可大致分為六類:分別為短鏈脂肪酸、hydroxamic acids、環狀胜肽、benzamides、親電性酮類以及其它。 本實驗室參考了目前已上市或仍在進行臨床試驗的HDAC inhibitors,發現N-hydroxyacrylamide及benzamide的官能基,是抑制活性的主要來源;另外,在觀察其他抗癌的小分子化合物中,含氮之雜環常作為core structure。是故,本實驗室決定探討含氮之[6,6]雜環作為主要的骨架,同時在其N位上以各種不同的苯 磺胺類及非苯磺胺類作取代,且在基本骨架上導入N-hydroxyacrylamide或benzamide官能基;同時,對於苯磺胺類的取代基以及連結上述兩個官能基的碳鏈作修飾,合成兩系列化合物,以了解HDAC抑制活性與結構之間的關係。 此次合成出之目標化合物中,以具有4’-甲氧基取代的苯磺胺類及官能基團為N-hydroxyacrylamide的化合物為最具抗癌活性。另一方面,將苯磺胺類的取代基改為鹵素原子或拉電子基基團,其抗癌活性皆下降;此外,官能基團為benzamide的目標化合物,其抗癌活性表現也為下降。此實驗日後仍會於本實驗室進行進一步的結構修飾,以期能合成出最具抗癌活性的目標化合物。

並列摘要


Histone deacetylase (HDAC) is related to the growth of cancer cell extremely. Not only used in cancer, it can be used a therapeutic target also in other diseases. The U. S. Food and Drug Administraction (FDA) approved the first histone deacetylase inhibitor (HDACi), SAHA (Vorinostat, Zolinza○R), used in the treatment of cutaneous T-cell lymphoma (CTCL) in 2006. Soon, FDA approved the second HDACi, FK228 (Romidepsin, Istodax○R), also used in the treatment of CTCL in the end of the 2009. There are still many HDACs undergoing the clinical trials, the compounds of this class have become the one of the research points of the anti-cancer drugs. HDACi is taken from the nature via extraction and purification and chemical synthesized. Basically, according to the structures, the HDACi can separate to six class, they are short-chain fatty acid, hydroxamic acids, cyclic peptides, benzamides, electrophilic ketones and others. After we compare the approved drugs and undergoing clinical trials compounds, we discover that the functional group of N-hydroxyacrylamide and benzamide is the source of inhibitory activity. Besides, the nitrogen-containing heterocycle is usually used as the core structure in other small molecular compounds of anti-cancer agents. Therefore, we decided to discover the nitrogen-containing [6, 6]-heterocycle as the core structure, and meanwhile, replace the substituted-phenyl sulfonamide and non-substituted-phenyl sulfonamide at N position. Also, introduce the functional group of N-hydroxyacrylamide or benzamide to the core structure. Furthermore, modify the carbon chain which connected the substituted groups and functional groups to synthesize two series compound to understand the relationship between inhibitory activity and the structure. In this experiment, the target compound which possesses the substitution group of 4’methoxy benzenesulfonamide and functional group of N-hydroxyacrylamide shows the best anti-tumor activity. On the other hand, changing the 4’methoxy group to the halogens or the nitro group shows the lower anti-tumor activity; others like changing the N-hydroxyacrylamide group to the banzamide group also shows the lower anti-tumor activity. Our lab will continue to modify the structure of the compounds of this experiment and try to synthesize the most potent compound as HDAC inhibitor.

參考文獻


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1. World Health Organization http://www.who.int/mediacentre/factsheets/fs297/en/index.html
3. U.S. Food and Drug Administration http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2006/ucm108758.htm
4. ClinicalTrials.gov http://clinicaltrials.gov/ct2/home

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