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標題: | 設計與合成喹唑啉-4-酮和3-芳香基吲哚衍生物作為潛能腫瘤抑制劑 Design and Synthesis of Quinazoline-4-one and 3-Arylindole Derivatives as Potential Anti-cancer Agents |
作者: | Chen-Jui Peng 彭楨芮 |
指導教授: | 陳基旺(Ji-Wang Chern) |
關鍵字: | 癌症,喹,唑啉,醯基羥胺,多靶, cancer,quinazoline,hydroxamic acid,multi-target, |
出版年 : | 2011 |
學位: | 碩士 |
摘要: | 為了發展強效的癌症抑制劑,相較於以往的單靶抑制劑,多重靶向抑制劑現今被認為有更好的抗癌潛力,故本論文以多重靶向抑制劑為主要設計概念,分別將紡錘體驅動蛋白 (KSP) 抑制劑、酪胺酸激酶 (RTK) 抑制劑與組蛋白去乙醯化酶 (HDAC) 抑制劑確效結構醯基羥胺官能基,結合作為起始模板,設計併合成 KSP 與 HDAC 雙效抑制劑,N-(1-(3-苯甲基-7-(3-(羥胺基)-3-氧代丙-1-己烯)-4-羰基-3,4-二氫基-2-喹唑啉基)丙基)-N-(3-(二甲氨基)丙基)苯甲醯胺 (9)。目標化合物 9 是將醯基羥胺官能基建構於喹唑啉-4-酮衍生物,可由2-氨基-4-氯苯甲酸與正丁酰氯、亞磷酸三苯酯和苯甲胺經由一鍋法微波反應進行合環得到3-苯甲基-7-氯-2-丙基喹唑啉-4 (3H)-酮 (13),化合物13再溴化得2-(1-溴丙基)-7-氯-喹唑啉-4 (3H)-酮 (12) ,12與3-二甲氨基丙胺加熱迴流可得3-苯甲基-7-氯-2-(1-(3-(二甲氨基) 丙基氨基) 丙基) 喹唑啉-4 (3H)-酮 (11),化合物11在一氧化碳環境下與碘化苯進行耦合反應得N-[1-(3-苯甲基-7-氯-4-羰基-3,4-二氫喹唑啉-2-基)丙基]-N-[3-(二甲氨基)丙基]苯甲醯胺 (8),化合物8利用微波進行海克反應,得到乙基-3-(3-苯甲基-2-(1-(N-(3-(二甲氨基)丙基)苯甲酰胺基)丙基)-4-羰基-3,4-二氫-7-喹唑啉)丙烯酸酯 (10),並進一步水解得 3-(3-苯甲基-2-(1-(N-(3-(二甲氨基)丙基)苯甲酰胺基) 丙基)-4-羰基-3,4-二氫喹唑啉-7-基)丙烯酸 (19),化合物19 與 O-(四氫-2H-吡喃-2-基)羥基胺反應得N-(1-(3-苯甲基-4-羰基-7-(3-羰基-3-(四氫-2H-吡喃-2-氧基氨基)丙基-1-己烯基)-3,4-二氫-2-喹唑啉基)丙基)-N-(3-(二甲氨基)丙基)苯甲醯胺 (20),最後以三氟醋酸切除保護官能基後以Sephadex LH-20進行分離純化目標化合物 9。在合成目標化合物 9 的同時,並以微波發展合成先導化合物 8,有效縮短總反應時間及提升合成總產率36倍。 RTK 與 HDAC 雙效抑制劑3-芳香基吲哚衍生物 24 是將醯基羥胺官能基建構於 3-芳香基吲哚衍生物,由6-氯吲哚酮為起始物依序經醇醛縮合反應、海克反應和官能基轉換而得,推測此類化合物結構呈現平面構形造成溶解度差,也許會導致活性測試上的偏差,故尚未進行後續活性測試。將合成出的唑啉-4-酮衍生物對胃癌細胞株 (AGS) 和腸癌細胞株 (HCT116) 進行體外癌細胞毒性測試,結果顯示目標化合物 9 具有癌細胞抑制活性 (AGS IC50 = 3.58 μM; HCT116 IC50 = 0.46 μM) ,雖然在 HDAC未如預期有抑制活性,但此類唑啉-4-酮衍生物作為癌症抑制劑具有發展潛力並值得繼續探索。 In order to explore more potent anti-cancer agent, multi-target inhibitors were regarded more potential than single target. A combination of the hydroxamic acid moiety in histone deacetylases (HDAC) inhibitors at active site with functional moieties of kinesin spindle protein (KSP) or receptor tyrosine kinase (RTK) inhibitors functional moieties were designed and synthesized based on this hypothesis. A potential multi-target inhibitor of KSP and HDAC, N-(1-(3-benzyl-7- (3-(hydroxyamino)-3-oxoprop-1-enyl)-4-oxo-3,4-dihydroquinazolin-2-yl)propyl)-N-(3-(dimethylamino)propyl)benzamide (9) was designed as preliminary compound with quinazoline-4-one scaffold bearing hydroxamic acid moiety. Compound 9 was synthesized through several steps including cyclization of 2-amino-4- chlorobenzoic acid with n-butyryl chloride and benzylamine via microwave-assisted one-pot reaction to provide 3-benzyl-7-chloro-2-propylquinazolin-4(3H)-one (13). Bromination of 13 provided 2-(1-Bromopropyl)-7-chloroquinazolin-4(3H)-one (12). Amination of 12 with 3-dimethylaminopropylamine provided 3-benzyl- 7-chloro-2-(1-(3-(dimethylamino)propylamino)propyl)quinazolin-4-(3H)-one (11). Compound 11 was coupled with iodobenzene under carbon monoxide to provide N-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)propyl]-N-[3-(dimethylamino)propyl]benzamide (8). Compound 8 was reacted with ethyl acrylate through microwave-assisted Heck reaction provide 3,4-dihydroquinazolin-7-yl)acrylate (10). Compound 10 was hydrolysis to provide 3-(3-benzyl-2-(1-(N-(3-(dimethylamino)propyl)benzamido)propyl)-4-oxo-3,4-dihydroquinazolin-7-yl) acrylic acid (19). Compound 19 was protected by O-(tetrahydro-2H-pyran-2-yl) hydroxylamine to provide N-(1-(3-benzyl-4-oxo-7-(3-oxo-3-(tetrahydro-2H-pyran- 2-yloxyamino)prop-1-enyl)-3,4-dihydroquinazolin-2-yl)propyl)-N-(3-(dimethylamino)propyl)benzamide (20). Finally, protecting group was cleaveged by trifluoroacetic acid and purified by Sephadex LH-20 to get compound 9. In the synthesis of target compound 9, reaction time was shorten and total yield was improvement in 36-folds comparing to original approach through microwave-assistance synthesis of KSP lead compound 8. 3-arylindole derivatives 24 were designed as RTK and HDAC dual inhibitors by combinating of hydroxamic acid with 3-arylindole scaffold and synthesized from 6-chlorooxindole via 3 steps. However, the solubilities of these series of compounds were poor, and led some difficulties in biological assays. Quinazoline-4-one derivatives were subjected to anti-proliferative activity against two human tumor cell lines (AGS and HCT116) by SRB assay. Compound 9 shows micromolar range inhibitory activity to these two cell line (AGS IC50 = 3.58 μM; HCT116 IC50 = 0.46 μM). Although 9 didn't demonstrate HDAC inhibition, the research suggested that quinazoline-4-one derivatives might serve as good lead compound for the development of anticancer agents. |
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