I.小分子抗癌藥物之開發 Ⅰ-1. 合成具有以吲哚修飾之 cap 之類似 SAHA 羥胺酸作為選擇性第一型組蛋白去乙醯酶抑制劑與探討其對腫瘤 細胞基因表現之效應 Ⅰ-2.合成以吖啶作為基礎之長鏈羥胺酸以作為組蛋白去乙醯酶及拓樸異構酶之雙標靶抑制劑 II.Hispidulin 之全合成及其對原致癌基因 Pim-1 抑制之結構基礎

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题名:	I.小分子抗癌藥物之開發 Ⅰ-1. 合成具有以吲哚修飾之 cap 之類似 SAHA 羥胺酸作為選擇性第一型組蛋白去乙醯酶抑制劑與探討其對腫瘤細胞基因表現之效應 Ⅰ-2.合成以吖啶作為基礎之長鏈羥胺酸以作為組蛋白去乙醯酶及拓樸異構酶之雙標靶抑制劑 II.Hispidulin 之全合成及其對原致癌基因 Pim-1 抑制之結構基礎 I.Development of small molecular anticancer drugs Ⅰ-1. Synthesis of SAHA-like hydroxamates with indole-modified cap as class I-selective HDAC inhibitors and their effects on gene expression of cancer cells Ⅰ-2.Synthesis and biological evaluation of acridine-derived aliphatic-chain hydroxamates dually targeting topoisomerase and histone deacetylaseII.Total synthesis of Hispidulin and the structural basis for its inhibition of Proto-oncogene kinase Pim-1
作者:	趙世偉 Chao, Shih-Wei
贡献者:	藥學系
关键词:	組蛋白去乙醯酶;標靶;激酶 histone deacetylases;target;kinase
日期:	2015-12-30
上传时间:	2021-01-07 10:22:06 (UTC+8)
摘要:	Ⅰ-1. 組蛋白去乙醯酶 (histone deacetylases, HDACs) 為一種酵素族群可調控表觀遺傳程序，其在生理活性扮演一個重要之角色與許多疾病上有相關性，臨床上顯示選擇性第I型組蛋白去乙醯酶 (class I HDACs) 抑制劑對癌症治療上有不錯之優點與低副作用。我們使用常見於抗癌藥物之scaffold trimethoxyindole 對SAHA 之 surface recognition cap 進行修飾。得到系列之化合物，進行組蛋白去乙醯酶酵素抑制試驗。其中化合物 6d-6f 及 6j-6m 在子宮頸癌細胞萃取之組蛋白去乙醯酶抑制活性優於SAHA 約 2.3-6 倍，而化合物 6d、6j 及 6k癌細胞抑制生長活性與與SAHA相當；組蛋白去乙醯酶isoform抑制活性測試顯示化合物6j 及 6k，與SAHA相較之下，具有更強之抑制在第I型組蛋白去乙醯酶之效果顯現出其為選擇性第I型組蛋白去乙醯酶抑制劑。 Ⅰ-2. 重標靶抗癌藥物藉由不同藥理之協同作用，減緩傳統單一標靶抗癌藥物所引起之抗藥性。我們混合 (hybridize) 選用臨床上使用之組蛋白去乙醯酶抑制劑 (HDAC)-SAHA 與文獻上報導之拓樸異構酶抑制劑 (topoisomerase)-DACA 之混成化學結構物，合成一系列長碳脂肪族羥基醯胺 (aliphatic hydroxamates)。與 SAHA 相較之下，許多化合物皆顯現較好的抑制組蛋白去乙醯酶活性 (anti-HDAC activity) 及癌細胞之細胞毒性 (cytotoxicity)，其中化合物 32d 更是表現最強之抑制於子宮頸癌細胞萃取之組蛋白去乙醯酶 (HeLa nuclear HDACs) 活性及數種癌細胞 (cancer cell lines)，更重要的是化合物 32d 呈現比 SAHA 更為廣效抑制組蛋白去乙醯酶 (HDAC)。此外，化合物 32d 能顯著地誘導組蛋白三型 (histone H3) 與 α-微管蛋白 (α-tubulin) 之乙醯化 (acetylation)，以及細胞週期檢測點激酶 1、2 型 (Chk1, Chk2) 之磷酸化 (phosphorylation)，說明化合物 32d 能有效抑制癌細胞之組蛋白去乙醯酶 (HDAC) 以及誘導DNA損傷 (DNA damage)，最後通過 ICE 檢測技術 (ICE assay) 證實化合物 32d 具有選性抑制拓樸異構酶一型 (topoisomeraseⅠ) 之活性，這些結果證實我們的設計將DACA 與 SAHA 之化學結構相混合 (hybridization) 可有效同時抑制組蛋白去乙醯酶(HDAC)與拓樸異構酶 (topoisomerase)。 II. Hispidulin 為具有多種活性之天然黃酮類 (flavone) 化合物，實驗發現 hispidulin 具有抑制致癌性蛋白激酶 (Pim-1 kinase) 之活性，且在 Pim-1 激酶 (Pim-1kinase) 與 hispidulin 結合之晶體結構分析上顯現與 quercetin 不同結合模式之處在於與激酶 (kinase) 樞紐區之氫鍵交互作用，產生不同抑制激酶 (kinase) 活性。總體來看，這樣的研究有利我們之後利用此合成方法建構由 hispidulin所衍生化合物之資料庫，以便探討黃酮類 (flavone) 與 Pim-1 激酶 (Pim-1 kinase) 抑制活性之結構與活性關係 (SAR). Ⅰ-1. Histone deacetylases (HDACs) are a family of enzymes that regulated epigenetic process. They play an important role in biological process and are associated with many diseases as well. Accumulating clinical studies indicate that class I–selective HDAC inhibitors offer therapeutic advantages and less side effects compared to traditional pan-HDAC inhibitors. In the study, we exploited a common scaffold in anticancer agents trimethoxyindole to modify the surface recognition cap of SAHA, a FDA-approved HDAC inhibitor. The resulting compounds were evaluated for their HDAC inhibitory activity against HeLa nuclear HDAC. Of these, compounds 6d-6f and 6j-6m showed 2.3-6 fold higher activity than SAHA. The cytotoxicities of compound 6d, 6j and 6k were comparable to those of SAHA. Further test of enzyme inhibition against individual HDAC indicated that compounds 6j and 6k exhibited anti-class I HDAC (1, -2, -3, -8) activity superior to SAHA, suggesting both compounds are class I-selective HDAC inhibitors. Ⅰ-2. The multiple target anticancer agents can provide a synergistic effect and overcome the drug resistance compared to traditional single target chemotherapeutics. We have hybridized the structure of a clinically used HDAC inhibitor SAHA and the reported topoisomerase inhibitor DACA to generate a novel series of aliphatic hydroxamates. Comparing to SAHA, several compounds exhibited higher anti-HDAC activity as well as superior cytotoxicity against cancer cells. One of these compounds, designated as compound 32d, showed the strongest activity towards HeLa nuclear HDACs and cancer cell lines. Importantly, it inhibited broader spectrum of HDAC than did SAHA. Additionally, compound 32d significantly induced acetylation of histone H3 and α-tubulin, and phosphorylation of Chk1 and Chk2. These results suggested that it inhibited HDAC and induced DNA damage in cancer cells. Through performing the ICE assay, compound 32d was confirmed as the selective topoisomerase I inhibitor. In conclusion, these results have revealed that effectiveness of our design concept by using hybridization of SAHA and DACA. II. A new method is applied to synthesize hispidulin, a natural flavone with a broad spectrum of biological activities. Hispidulin exhibits inhibitory activity against the oncogenic protein kinase Pim-1. Crystallographic analysis of Pim-1 bound to hispidulin reveals a binding mode distinct from that of quercetin, suggesting that the binding potency of flavonoids is determined by their hydrogen-bonding interactions with the hinge region of the kinase. Overall, this work may facilitate construction of a library of hispidulin-derived compounds for investigating the structure-activity relationship (SAR) of flavone-based Pim-1 inhibitors.
描述:	博士指導教授:黃偉展委員:顧記華委員:張崇毅委員:蕭哲志委員:侯文琪
数据类型:	thesis
显示于类别:	[藥學系] 博碩士論文

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