6-烷胺基-2-取代苯基-4-喹啉酮衍生物之合成與細胞致毒活性

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Title:	6-烷胺基-2-取代苯基-4-喹啉酮衍生物之合成與細胞致毒活性 Synthesis and cytotoxicity of 6-alkylamino-2-substituted phenyl-4-quinolone derivatives
Authors:	陳明華;Ming-Hua Chen
Contributors:	藥學院藥物化學研究所碩士班
Keywords:	phosphate前藥;抗癌;喹啉酮;phosphate-prodrugs;anti-cancer;quinolone
Date:	2010
Issue Date:	2010-09-29 14:10:35 (UTC+8)
Abstract:	在我們先前的研究中發現3’-methoxy-6-alkylamino-2-phenyl-4- quinolone為非常有效的細胞致毒藥物，此化合物於動物體內評估試驗時，其最大容忍劑量中證實屬於中等程度之抗腫瘤活性。為了尋找更安全的抗腫瘤藥物，因此設計一系列6-alkylamino-2-hydroxyphenyl-4-quinolone衍生物。這些標的化合物根據之前已知方法進行合成，將5-alkylamino-2-aminoacetophenone (4a-4c) 與substituted benzoyl chloride (28-35)反應得到相對應之biaryl amide (36-44)中間產物，之後於1,4-dioxane中強鹼NaOH存在下進行環化反應，即得到其2-phenyl-4-quinolone類衍生物(45-53)。將其中化合物(45-48、51)分別以Pd/C當催化劑進行氫化反應或以強酸溴化氫進行去甲基化反應，即得標的化合物(54-57、60)。以數種人類癌細胞株評估這些新合成的6-烷基-2-氫氧苯基-4-喹啉酮(54-57、60) 衍生物之細胞致毒活性，其結構與活性之關係將進一步被證實。初步的藥理結果顯示化合物 3’-hydroxy-6-morpholinyl-2-phenyl-4- quinolone (55a) 、3’-hydroxy-6-pyrrolidinyl-2-phenyl-4-quinolone (55b) 以及3’-hydroxy-6-dimethylamino-2-phenyl-4-quinolone (55c) 對人類血癌細胞株HL-60具有相當優異的細胞致毒活性 (IC50介於0.23-0.009 μM)，且對人類正常細胞株Detriot 551毒性明顯下降，適合未來進行評估之新的先導化合物。 In our previous study , 2-(3’-methoxyphenyl)-6-alkylaminoquinolin-4-one (1) was identified as a potent cytotoxicity agents. Compound 1 was evaluated at a maximally tolerance dose with evidence of moderate antitumor activity. In order to search safer antitumor agents , a series of 6-alkylamino- 2-hydroxyphenyl-4-quinolone derivatives were designed and synthesized. Following published methods , 5-alkylamino-2-aminoacetophenone (4a-4c) were reacted separately with substituted benzoyl chloride (28-35) to yield the correspounding biaryl amide (36-44) which were subsequently cyclized in 1,4 dioxane in the presence of NaOH to give the correspounding substituted 2-phenylquinolin-4-one (45-53). Compounds (45-48、51) were catalytic hydrogenation or demethylated by HBr to afford the correspounding trarget compounds(54-57、60). The newly synthesized 6-alkylamino-2-hydroxyphenyl-4-quinolone dervatives (54-57、60) were evaluated for cytotoxicity against several human cancer cell lines. The structure-activity relationship was discussed. Preliminary results showed that 3’-hydroxy-6-morpholinyl-2-phenyl-4- quinolone (55a)、3’-hydroxy-6-pyrrolidinyl-2-phenyl-4-quinolone (55b) and 3’-hydroxy-6-dimethylamino-2-phenyl-4-quinolone (55c)have potent cytotoicity (IC50 values of 0.23-0.009 μM) against HL-60 leukemia cancer cell line with low toxicity against Detroit 551 normal human cell line. These target compounds will be used as new lead compounds for further evaluation.
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