| 刘斌,徐小娜,仝红娟,唐文强,王艳娇.化学通报,2022,85(5):613-618. |
| 含4-氨基哌啶片段的6,7-二甲氧基喹啉衍生物的合成及抗肿瘤活性 |
| Synthesis and Anti-tumor Activity of 6,7-Dimethoxyquinoline Derivatives Containing 4-Aminopiperidine Moiety |
| 投稿时间：2021-08-27 修订日期：2021-09-27 |
| DOI： |
| 中文关键词: 6,7-二甲氧基喹啉 4-氨基哌啶 1-异丙基哌啶-4-胺 Buchwald-Hartwig偶联反应 抗肿瘤活性 |
| 英文关键词:6,7-dimethoxyquinoline 4-aminopiperidine 1-isopropylpiperidin-4-amine Buchwald-Hartwig coupling reaction antitumor activity |
| 基金项目:陕西省自然科学基础研究计划(面上)项目(2021JM-540),陕西省中药绿色制造技术协同创新中心重点培育项目(2019XT-1-05),陕西省教育厅专项科研计划项目(21JK0510)；陕西国际商贸学院“中药药效物质研究”创新团队资助项目(SSY18TD01)。*通讯联系人：刘斌(1982-),男,博士,讲师,研究方向：药物分子设计合成. E-mail: lb125lb@163.com. ,徐小娜2,仝红娟1,唐文强1,王艳娇1 |
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| 中文摘要: |
| 以2-氨基-4,5-二甲氧基苯甲酸（2）和环酮（环戊酮、环己酮）为原料，在三氯氧磷作用下“一锅法”合成6,7-二甲氧基喹啉中间体（3），再与4-氨基哌啶或4-异丙基环己烷-1-胺（4）发生Buchwald-Hartwig偶联反应，得到含有4-氨基哌啶或4-异丙基环己烷-1-胺片段的6,7-二甲氧基喹啉衍生物（1a~1f），4-(6,7-二甲氧基-1,2,3,4-四氢吖啶-9-基)氨基哌啶-1-甲酸叔丁酯（1e）在酸性条件下脱除Boc保护基得到6,7-二甲氧基-N-(哌啶-4-基)-1,2,3,4-四氢吖啶-9-胺（1g），产物及中间体结构通过1H NMR、13C NMR、MS及元素分析表征。并筛选确定该Buchwald-Hartwig偶联反应的最佳反应条件为：反应溶剂为甲苯；催化剂为BrettPhos-Pd-G3；物料比为n（4a）: n（3a）= 1.2 : 1；反应温度为100℃。随后，初步的抗肿瘤活性测试结果表明，目标化合物1对HepG2、MCF-7、PC3和HeLa均有明显的抑制活性，尤其是化合物1b（IC50 = 11.2 μmol/L）展现出了较强的MCF-7抑制活性，甚至强于当前乳腺癌的一线治疗药物4-羟基他莫昔芬 (IC50 = 15.1 μmol/L)，同时是先导化合物3b和4a的2.2和2.7倍；此外，目标化合物对正常的乳腺上皮细胞MCF-10A没有毒性。 |
| 英文摘要: |
| Using 2-amino-4,5-dimethoxybenzoic acid (2) and aliphatic cyclic ketone (cyclopentanone, cyclohexanone) as starting materials, 6,7-dimethoxyquinoline intermediate (3) was synthesized by a one-pot method in the presence of phosphoryl trichloride. Then, the 6,7-dimethoxyquinoline derivatives containing 4-aminopiperidine or 4-isopropylcyclohexan-1-amine moiety were obtained by Buchwald-Hartwig coupling reaction of intermediate (3) with 4-aminopiperidine or 4-isopropylcyclohexan-1-amine (4). Under acidic conditions, 6,7-dimethoxy-N-(piperidin-4-yl)-1,2,3,4-tetrahydroacridin-9-amine (1g) was obtained by removing the Boc protecting group of tert-butyl 4-((6,7-dimethoxy-1,2,3,4-tetrahydroacridin-9-yl)amino)piperidine- 1-carboxylate (1e). The structures of the products and intermediates were characterized by 1H NMR, 13C NMR, MS and elemental analysis. The optimum conditions for the Buchwald-Hartwig coupling reaction are as follows: the reaction solvent was toluene; the catalyst was BrettPhos-Pd-G3; the material ratio was n (4) : n (3) = 1.2 : 1; the reaction temperature was 100 ℃. Subsequently, the preliminary anti-tumor activity test results showed that the target compound 1 exhibited significant inhibitory activity against HepG2, MCF-7, PC3 and HeLa. Especially, compound 1b (IC50 = 11.2 μmol/L) exhibited the strongest inhibitory activity against MCF-7, which was even stronger than the current first-line treatment of breast cancer, 4-hydroxytamoxifen (IC50 = 15.1 μmol/L), and which was 2.2 and 2.7-folds than lead compounds 3b and 4a; moreover, compound 1 was no toxic to normal mammary epithelial cells MCF-10A. |
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