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研究生(外文):Chin-Yu Liu
論文名稱(外文):Synthesis and Anticancer Activity of 2-(3-Hydroxyphenyl)-5-methyl-1,8-naphathyridin-4(1H)-one and its Related Compounds
指導教授(外文):Sheng-Chu Kuo
外文關鍵詞:Hydroxy substituted 2-aryl-18-naphathyridin-4-onephosphate prodrugHep3B cancer cell line
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第一部分:為了從2-aryl-1,8-naphthyridin-4-ones(2-AN)系列化合物探索新抗癌候選藥物,著者設計並合成了一系列3′-hydroxy或6-hydroxy取代的2-AN衍生物,其中大部分的化合物對腫瘤細胞株都展現了顯著的細胞毒性,尤其是2-(3-hydroxyphenyl)-5-methyl-1,8-naphathyridine- 4(1H)-one(7a)最具發展潛力,初步的藥理作用機轉結果顯示7a影響Hep3B細胞株之微管及轉移相關蛋白,另外化合物7a的磷酸化前驅藥11,對Hep3B xenograft animal model展現顯著的抗腫瘤活性,因此化合物11深具潛力足以繼續進行臨床前研究。
第二部分:本研究的主要目的在探討KHL-1抑制肝細胞癌細胞株Hep3B細胞生長之作用機制。利用cDNA微陣列與西方點墨法去偵測KHL-1所造成的基因與蛋白表現變化。結果顯示,KHL-1會造成Hep3B細胞生長抑制、細胞形態改變、細胞週期G2/M期停滯,以及細胞凋亡作用。cDNA 微陣列分析結果顯示,許多與細胞生長、血管新生、細胞自噬作用、鈣離子引起的內質網壓力相關訊息路徑、細胞黏附作用、細胞週期、減數分裂、細胞移行作用、細胞骨架排列、DNA損壞與修復、粒腺體凋亡,以及細胞訊號路徑相關的基因表現量會受到KHL-1的影響。此外,KHL-1會降低CDK1活性、增加細胞內鈣離子濃度、caspase-4、caspase-9 與caspase-3的活性。西方點墨法結果顯示,KHL-1會增加caspase-4與GADD153的蛋白表現量,這可能會促使內質網壓力增加,進而促進Hep3B細胞的凋亡作用。因此,KHL-1經由促使G2/M期停滯、鈣離子增加引起的內質網壓力,以及活化粒腺體凋亡路徑等機制,以抑制Hep3B細胞的生長。

Part1:To develop new antitumor drug candidates from 2-aryl-1,8- naphthyridin-4-ones (2-AN), we have designed and synthesized 3''-hydroxy or 6-hydroxy 2-AN derivatives. Most of the new compounds exhibited significant cytotoxicity against cancer cell lines. Among them, 2-(3-hydroxyphenyl)-5-methyl-1,8-naphthyridin-4(1H)-one (7a) was the most promising. In the preliminary mechanism of action study, treatment of Hep3B hepatoma cells with 7a showed effects on microtubules and metastasis-related proteins. In addition, the phosphate prodrug 11 of 7a exhibited significant antitumor activity when tested in a Hep3B xenograft nude mice model. Therefore, compound 11 has good development potential and is recommended for further preclinical studies.
Part2:In the present study, we investigated the antitumor effects of KHL-1 on the viability, cell cycle and apoptotic cell death in human epatocellular carcinoma Hep3B cells in vitro. We also investigated the molecular mechanisms involved in the effects of KHL-1 on human hepatoma Hep3B cells, including the effects on protein and mRNA levels which were determined by western blotting and DNA microarray methods, respectively. The results demonstrated that KHL-1 induced growth inhibition, cell morphological changes and induction of G2/M arrest and apoptosis in Hep3B cells. DNA microarray assay identified numerous differentially expressed genes related to angiogenesis, autophagy, calcium-mediated ER stress signaling, cell adhesion, cell cycle and mitosis, cell migration, cytoskeleton organization, DNA damage and repair, mitochondrial-mediated apoptosis and cell signaling pathways. Furthermore, KHL-1 inhibited CDK1 activity, mitochondrial membrane potential (ΔΨm) and increased the cytosolic Ca2+ release and caspase-4, caspase-9 and caspase-3 activities in Hep3B cells. Western blot analysis demonstrated that KHL-1 increased the protein levels of caspase-4 and GADD153 that may lead to ER stress and consequently apoptosis in Hep3B cells. Taken together, KHL-1 acts against human hepatocellular carcinoma Hep3B cells in vitro through G2/M phase arrest and induction of calcium-mediated ER stress and mitochondrial-dependent apoptotic signaling pathways.

第一章 緒論.....1
第一節 2-Aryl-1,8-naphthyridin-4(1H)-one類化合物.....1
第二節 Phosphate prodrug之特性.....13
第二章 研究動機與目的.....17
第三章 結果與討論.....19
第一節 標的化合物之合成.....19
第二節 藥理活性測試結果.....39
第四章 結論.....68
第五章 實驗部分.....69
第一節 試藥與溶媒.....69
第二節 重要儀器與實驗材料.....74
第三節 各化合物之製備.....77
第四節 藥理實驗方法.....123
第一章 緒論.....159
第一節 細胞週期.....159
第二節 細胞凋亡.....162
第三節 內質網壓力.....164
第二章 研究動機與目的.....166
第三章 結果與討論.....167
第一節 KHL-1的製備.....167
第二節 藥理活性實驗結果.....169
第四章 結論.....189
第五章 實驗部分.....190
第一節 試藥與溶媒.....190
第二節 重要儀器與實驗材料.....194
第三節 目標化合物之製備.....196
第四節 化合物之光譜資料.....199
第五節 藥理實驗方法.....202

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