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研究生:劉宜旻
研究生(外文):Yi-Min Liu
論文名稱:壹、合成苯磺雜環類緣物抗癌劑的研究貳、合成目標基礎小分子抗癌劑的研究
論文名稱(外文):I. Synthesis of arylsulfonylheterocycles analogs as anti-cancer agentsII. Synthesis of target-based small molecules as anti-cancer agents
指導教授:劉景平劉景平引用關係
指導教授(外文):Jing-Ping Liou
口試委員:陳繼明楊家榮葉燈光潘秀玲
口試委員(外文):Chi-Ming ChenChia-Ron YangTeng-Kuang YehShiow-Lin Pan
口試日期:2015-12-30
學位類別:博士
校院名稱:臺北醫學大學
系所名稱:藥學系(碩博士班)
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2016
畢業學年度:104
語文別:中文
論文頁數:571
中文關鍵詞:苯磺雜環類緣物抗癌劑
外文關鍵詞:arylsulfonylheterocycles analogsanti-cancer agents
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組蛋白去乙醯酶(histone deacetylase, HDAC)、熱休克蛋白(heat shock protein)、纖維細胞生長因子(fibroblast growth factor, FGF)以及DNA連接酶(E3 ligase)與癌細胞的生長有著相當大的關聯。針對這些目標進行研究,不僅可用於癌症治療中,同時也可以對其他疾病作為治療標靶。

組蛋白去乙醯酶抑制劑(histone deacetylase inhibitor, HDACi)截至目前為止,美國FDA (Food and Drug Administration)已經核准通過四個藥物上市,分別用於治療T細胞淋巴癌(T-cell lymphoma)和多發性骨髓瘤(multiple myeloma)。目前仍有上百個HDACi相關的臨床實驗進行中,此類藥物也因而成為了抗癌藥物研發重點之一。

現今的HDACi大多是從天然物中萃取純化取得或是由化學合成而得,依據結構的不同可大致分為六類,其中最大的兩類則是hydroxamic acids以及benzamides,皆是化合物活性的主要來源。本實驗室參考了目前已經上市的藥物以及實驗室先前的研究成果,決定探討含氮之[6,6]以及[6,5]雜環作為主要的骨架,在N位上作一系列不同官能基的芳香磺胺類類緣物作取代,同時導入hydroxamic acids以及benzamides官能基且在其連接的碳鏈上作修飾及變化。共合成三系列化合物,以了解HDAC抑制活性與結構之間的關係。

同時,近年來有不少文獻提出「選擇性HDAC 6」的化合物的觀念。經由文獻的閱覽之後,在十一種isoform當中,HDAC 6的特性較為獨特。因此,本實驗室決定利用5-氟尿嘧啶類緣物作為主要骨架,在N位上導入hydroxamic acids以及benzamides官能基且在其連接的碳鏈上作修飾及變化,以了解化合物是否具有選擇性以及HDAC抑制活性,並了解其與結構之間的關係。

熱休克蛋白抑制劑(heat shock protein inhibitor, HSPi)之中,較被廣泛研究的為HSP90 inhibitor,其致病機轉也在近幾年之中探求而有所得並同時顯示出其與惡性腫瘤的生成非常相關。雖然目前尚未有藥物通過核可上市,但是這一類的化合物也有將近二十個正在進行臨床試驗,顯現出未來其可成為抗癌藥物的發展重點之一。

本實驗室參考了目前幾個仍在進行臨床試驗的化合物以及先前實驗室的研究成果,發現2,4-二羥基類緣物具有很強的抑制效果,故決定探討導入各種不同的含氮雜環作為主要骨架,以了解HSP抑制活性與結構之間的關係。

纖維細胞生長因子(fibroblast growth factor, FGF)除了參與細胞生長的訊息傳遞之外,目前也已廣泛得知其在血管新生作用之中扮演相當大的角色,也證實其與多種固態腫瘤的生成皆有關聯。在現在的臨床試驗當中,依據選擇性的有無,可劃分為第一代以及第二代的纖維細胞生長因子接受器抑制劑(FGF receptor inhibitor, FGFRi)的化合物,尤以具備選擇性之第二代的化合物表現出高度活性,可提供作為未來發展成為新穎的抗癌藥物。
本實驗室參考了目前進入臨床試驗,且為第二代具選擇性化合物的結構,決定探討利用各種不同的含氮雜環作為主要結構,以了解FGFR抑制活性與結構之間的關係。

DNA連接酶( E3 ligase)是人體中其中一種ligase,屬於非常大且複雜的super-family protein,主要參與著人體內物質的分解過程,且與蛋白酶體(proteasome)的作用息息相關。目前E3 ligase較深入的作用機轉仍尚未確立,且其對於受質的連接方式也還不明確,但現今已有不少發表的文獻表示E3 ligase與人類疾病有關。目前為止,仍尚未有較為顯著的小分子藥物出現並進入到臨床實驗階段。但相對而言,這一類的化合物具有相當大的潛力可作為將來新穎抗癌藥物的發展。

本實驗室參考了目前已有文獻發表之化合物結構,決定探討利用1,4-二酮萘環作為主要架構,導入各種不同的含氨類雜環作官能基團的修飾,並同時對連接部分的碳鏈加以修飾及變化構形,以了解E3 ligase抑制活性與結構之間的關係。

根據各項不同的系列的活性數據顯示,化合物II-17以及II-51具有高度抑制HDAC活性,且於動物實驗中具有明顯抑制腫瘤生長的效果。化合物III-14則是具有高度的選擇性抑制HDAC 6的活性,並於動物實驗中明顯表現出抑制腫瘤生長。化合物IV-23c、V-19c及VI-35e分別針對於HSP90、FGFR以及E3 ligase為目標,皆於細胞實驗中表現出了良好的抗癌活性。期許這些化合物都能夠在各個不同的目標系列中,進一步發展成為先導化合物,或是提供一個全新的思考方向,於將來能夠具有更多發展這些化合物的機會。
Histone deacetylase (HDAC), Heat shock protein (HSP), fibroblast growth factor (FGF) and E3 ligase are related to the growth of cancer cell extremely. Not only used in cancer, it could be used as a therapeutic target also in other diseases.

Up to date, there are four histone deacetylase inhibitors (HDACis) have been approved by the U. S. Food and Drug Administration (FDA) and used in the treatment of T-cell lymphoma and multiple myeloma. Meanwhile, hundreds of clinical trials are still undergoing, 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. According to their structures, the top two groups are hydroxamic acids and benzamides, both of these two functional groups are the source of HDAC inhibitory activity. After we referred to the approved drugs and the effort from our laboratory, we decided to discover the nitrogen-containing [6,6]- and [6,5]-heterocycles as the core structure, and meanwhile, introduce the substituted-aryl sulfonamides with different groups at N position. Also, introduce the hydroxamic acids and benzamides as the functional groups to the core structure. Furthermore, modify the carbon chain which connected the substituted groups and functional groups to synthesize three different series compound to understand the relationship between inhibition activity and the structure.

Recently, ‘selective HDAC 6’ was mentioned in many references. After reading these references, we found that the HDAC 6 in all the HDAC isoforms plays a unique role. We decided to discover the 5-fluorouracil analogs as the core structure. Introduce the hydroxamic acids and benzamides as the functional groups to the N position and modify the carbon chain which connected the functional groups to synthesize a series compound to figure out the ‘selective HDAC 6’ and the relationship between inhibition activity and the structure.

The HSP90 inhibitors (heat shock protein 90 inhibitors) was been widely researched in all of the HSP inhibitors. The mechanism has been discovered in these decades and related to the growth of malignant tumors exceptionally. Until now, there are no any drugs of this class in the market. However, there are at least twenty clinical trials undergoing which reveal that HSP90 inhibitors will become one of the research points of the anti-cancer drugs in the future.

We referred to the drugs which entered into clinical trials and the effort from our laboratory and discover that 2,4-dihydroxy analogs has the strong inhibition effect. We decided to introduce different nitrogen-containing heterocycles as the core structure to understand the relationship between inhibition activity and the structure.
Fibroblast growth factor (FGF) is not only involving the signal communication of cell growth but also playing an important role in the angiogenesis. Meanwhile, FGF has also found the connection with the growth of several solid tumors. According to the selectivity or not, the FGF receptor inhibitor (FGFRi) can classified to first and second generation compounds in clinical trials. The second generations which possess the selectivity show the high inhibition activity and provide a way to develop the novel anti-cancer drugs.

We referred to the compounds which entered into clinical trials and possessed the selectivity. We decided to introduce different nitrogen-containing heterocycles as the core structure to understand the relationship between FGFR inhibition activity and the structure.

E3 ligase is one of the DNA ligase in human and is a very big and complex super-family protein. The E3 ligase is mainly involving in the degradation process of substrate in body and related to the action of proteasome. Up to date, the detail mechanism of E3 ligase has not been confirmed and also unclear in the connection of substrates. Though there are many references have been published and exhibited that E3 ligase is related to human diseases, but there is still no any small molecular compound that have successfully entered into clinical trials. On the other hand, the compounds of this class have the powerful potential to develop as the novel anti-cancer drugs.

We referred to the compounds which have been published recently. We decided to use the naphthalene-1,4-one as the core structure and introduce different nitrogen-containing heterocycles as the functional group. In addition, change and modify the carbon chain which connected the substituted groups and functional groups to synthesize one series compound to understand the relationship between inhibition activity and the structure.

According to activity data of different series, compound II-17 and II-51 have shown good HDAC inhibitory activity. Both of these compounds have displayed the effect of tumor growth inhibition in the animal model. Compound III-14 has shown good activity and selectivity on HDAC 6 and also exhibited the tumor growth inhibition in xenograft model. Compound IV-23c, V-19c and VI-35e have shown good activity on HSP90, FGFR and E3 ligase inhibition, respectively. We hope that these compounds can become lead compounds or provide a whole new thought in every different target-based series as well as to get more chances to develop all the synthetic compounds.
Index

Index......................................................................................................................................... I
Index of tables.......................................................................................................................... II
Index of figures......................................................................................................................... IV
Index of schemes...................................................................................................................... VIII
Abstract.................................................................................................................................... IX
Chapter I Introduction...................................................................................................... 001
Chapter II Synthesis of N-containing heterocycles analogs as novel classes of histone deacetylase inhibitors.......................................................................................
016
Chapter III Synthesis of uracil-containing analogs as novel class of selective HDAC 6 inhibitors...........................................................................................................
063
Chapter IV Synthesis of N-containing heterocycles analogs as novel class of heat shock protein 90 inhibitors..........................................................................................
080
Chapter V Synthesis of pyrimidine-based heterocycles analogs as novel class of the fibroblast growth factor family of receptor tyrosine kinase inhibitors...........................................................................................................

101
Chapter VI Synthesis of naphthoquinone-based heterocycles analogs as novel E3 ligase inhibitors...........................................................................................................
128
Chapter VII Experimental section......................................................................................... 155
Chapter VIII Synthetic procedures of all the synthetic compounds in chapter II-VI.............. 162
VIII.1. Synthetic procedures of all the synthetic compounds in chapter II........ 162
VIII.2. Synthetic procedures of all the synthetic compounds in chapter III....... 206
VIII.3. Synthetic procedures of all the synthetic compounds in chapter IV....... 215
VIII.4. Synthetic procedures of all the synthetic compounds in chapter V........ 234
VIII.5. Synthetic procedures of all the synthetic compounds in chapter VI....... 264
Chapter IX References......................................................................................................... 298

Appendix 1H Spectrums of all the synthetic compounds in chapter II-VI.......................... 307
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