六氢-1H-吡咯并[3,4-d]嘧啶衍生物的合成及抗肿瘤活性

doi:10.11944/j.issn.1000-0518.2017.05.160191

摘要/Abstract

摘要：

以顺丁烯二酸酐为原料,经过水解、缩合、库尔提斯重排、脱保护得到1-苄基-3-氨基-吡咯烷-4-羧酸甲酯盐酸盐,再与硫脲衍生物缩合得到1-苄基-4-(2-甲酸叔丁酯-3-胍基)吡咯烷-3-羧酸甲酯衍生物,最后经过水解、酯化、脱保护得到六氢-1H-吡咯并[3,4-d]嘧啶衍生物,其结构经¹H NMR、¹³C NMR、ESI-MS和元素分析表征。 3-(4, 5-二甲基噻唑-2)-2,5-二苯基四氮唑溴盐(MTT)法测试其抗肿瘤活性,实验结果表明,其中化合物9d和9g对肿瘤细胞(Bel-7402)株具有明显的抑制活性。

关键词: 顺丁烯二酸酐, 库尔提斯重排, 六氢-1H-吡咯并[3,4-d]嘧啶衍生物, 抗肿瘤活性

Abstract:

Using maleic anhydride as the starting material, hexahydro-1H-pyrrolo[3,4-d] pyrimidine derivatives were synthesized. The structures of all compounds were characterized by ¹H NMR, ¹³C NMR, ESI-MS and elemental analysis. Their antitumor activities against Bel-740 human liver cancer cells were determined by the 3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-di-phenytetrazoliumromide(MTT) assay. The results indicate that these compounds have a certain inhibitory activity in Bel-740 human liver cancer cells, and the inhibitory activity of compounds 9d and 9g reach the average level.

Key words: maleic anhydride, curtius rearrangement, hexahydro-1H-pyrrolo [3,4-d] pyrimidine derivatives, antitumor activity

李娜,李辉. 六氢-1H-吡咯并[3,4-d]嘧啶衍生物的合成及抗肿瘤活性[J]. 应用化学, 2017, 34(5): 541-549.

LI Na,LI Hui. Synthesis and Antitumor Activity of Hexahydro-1H-pyrrolo [3,4-d] Pyrimidine Derivatives[J]. Chinese Journal of Applied Chemistry, 2017, 34(5): 541-549.

参考文献

[1]	Tumkevicius S,Urbonas A,Vainilavicius P. Synthesis of Methyl Esters of 5-Amino-4-(substituted amino)-2-methylthio-7H-pyrrolo[2,3-d]-pyrimidine-6-carboxylic Acids[J]. Chem Heterocycl Compd,2000,36(7):841-846.
[2]	Renau T E,Kennedy C,Ptak R G,et al. Synthesis of Non-nucleoside Analogs of Toyocamycin, Sangivamycin, and Thiosangivamycin:The Effect of Certain 4- and 4,6-Substituents on the Antiviral Activity of Pyrrolo[2,3-d]pyrimidines[J]. J Med Chem,1996,39(19):3470-3476.
[3]	Simone M,Erba E,Damia G,et al. Variolin B and its Derivate Deoxy-variolin B:New Marine Natural Compounds with Cyclin-dependent Kinase Inhibitor Activity[J]. Eur J Cancer,2005,41(15):2366-2377.
[4]	Gangjee A,Yang J,Mcguire J J,et al. Synthesis and Evaluation of a Classical 2,4-Diamino-5-substituted-furo[2,3-d]pyrimidine and a 2-Amino-4-oxo-6-substituted-pyrrolo[2,3-d]pyrimidine as Antifolates[J]. Bioorg Med Chem,2006,14(24):8590-8598.
[5]	Gangjee A,Vidwans A,Elzein E,et al. Synthesis, Antifolate, and Antitumor Activities of Classical and Nonclassical 2-Amino-4-oxo-5-substituted-pyrrolo[2,3-d]pyrimidines[J]. J Med Chem,2001,44(12):1993-2003.
[6]	FAN Bolin. Novel Angiogenesis Inhibitors:Design, Synthesis and Biological Activites of Thalidomide Analogs [D].Shanghai:Shanghai Jiaotong University,2008(in Chinese). 范柏林. 新型血管生成抑制剂—沙利度胺(THD)类似物的设计、合成及其生物活性研究 [D]. 上海:上海交通大学,2008.
[7]	Srikanth K,Debnath B,Jha T. QSAR Study on Adenosine Kinase Inhibition of Pyrrolo[2,3-d]pyrimidine Nucleoside Analogues Using the Hansch Approach[J]. Bioorg Med Chem Lett,2002,12(6):899-902.
[8]	Ugarkar B G,Dare J M,Kopcho J J,et al. Synthesis, Enzyme Inhibition, and Antiseizure Activity of 5-Iodotubercidin Analogue[J]. J Med Chem,2000,43(15):2883-2893.
[9]	Richard H F,Peter C T,Schramm V. Nucleoside Metabolism Inhibitors:US 0015772[P],2007.
[10]	WANG Guoqiang,DUAN Nannan,CAO Tieyao,et al. Antitumor Fluoroquinolone C3-isostere Derivatives(I)-synthesis and Activity of Bis-oxadiazole Methyl-sulfide Derivatives[J]. Chinese J Appl Chem,2012,29(7):769-774(in Chinese). 王国强,段楠楠,曹铁耀,等. 抗肿瘤氟喹诺酮C3等排衍生物(Ⅰ)-双噁二唑甲硫醚衍生物的合成和抗肿瘤活性[J]. 应用化学,2012,29(7):769-774.
[11]	YANG Ruisheng,HU Guoqiang,XIE Songqiang,et al. Synthesis and Antitumor Activity of 3-Methylthio-4-amino-5-pyridin-3-yl-1,2,4-triazole Schiff Bases[J]. Chinese J Appl Chem,2008,25(7):783-786(in Chinese). 杨锐生,胡国强,谢松强,等. 3-甲硫基-4-氨基-5-(吡啶-3-基)-1,2,4-三唑席夫碱的合成及抗肿瘤活性[J]. 应用化学,2008,25(7):783-786.
[12]	LUO Wen,LI Zhan,ZHAI Yangyang,et al. Synthesis and Antitumor Activity of Polyamine Derivatives of Naphthalimide[J]. Chinese J Appl Chem,2013,30(3):265-270(in Chinese). 罗稳,李展,翟洋洋,等. 萘酰亚胺多胺衍生物的合成及其抗肿瘤活性[J]. 应用化学,2013,30(3):265-270.
[13]	LI Shining,SUN Chunling,ZHANG Dandan,et al. Synthesis of 5,6,7,8-Tetrahydropyrido [3,4-d]pyrimidine derivatives[J]. Chem Res Appl,2016,28(2):164-169(in Chinese). 李世宁,孙春玲,张丹丹,等. 5,6,7,8-四氢吡啶并[3,4-d] 嘧啶衍生物的合成[J]. 化学研究与应用,2016,28(2):164-169.
[14]	Chaumontet M,Piccardi R,Baudoin O. Synthesis of 3,4-Dihydroisoquinolines by a C(sp(3))—H Activation/Electrocyclization Strategy:Total Synthesis of Coralydine[J]. Angew Chem Int Ed, 2009,48(1):179-182.

[1]	张会丽, 崔红艳, 黄文龙, 胡国强. 饶丹宁甲叉基取代左氧氟沙星衍生物的合成与抗肿瘤活性[J]. 应用化学, 2021, 38(2): 188-194.
[2]	吴学姣, 苟光淋, 杨小兰, 杨家强. 二肽类膦酸酯衍生物的合成与抗肿瘤活性[J]. 应用化学, 2021, 38(1): 36-43.
[3]	张思佳, 徐彩娜, 陈杰, 田华雨, 陈学思. 通过调控肿瘤代谢增强T细胞抗肿瘤活性[J]. 应用化学, 2020, 37(9): 977-984.
[4]	张会丽, 崔红艳, 黄文龙, 胡国强. 左氧氟沙星3-芳苄叉基-喹啉-4-酮衍生物的合成及抗肿瘤活性[J]. 应用化学, 2020, 37(12): 1426-1431.
[5]	宫益林, 史建涛, 王洋, 陈烨, 丁实, 刘洋, 刘举. 新型吲唑-查尔酮杂合物的合成及抗肿瘤活性[J]. 应用化学, 2019, 36(9): 1015-1022.
[6]	张会丽, 李珂, 黄文龙, 王蕊, 胡国强. N-(5-芳苄叉基饶丹宁)左氧氟沙星酰胺的合成及抗肿瘤活性[J]. 应用化学, 2019, 36(8): 897-903.
[7]	李元元,张呈霞,黄文龙,陈超然,胡国强. 左氧氟沙星的噻唑并均三唑衍生物的合成及抗肿瘤活性[J]. 应用化学, 2019, 36(6): 671-676.
[8]	桂舒雅,熊昊,林智,夏霖亚,钟启升,李东风,侯瑞斌,夏艳. 新型含有金刚烷苯乙烯结构单元化合物的合成和初步抗肿瘤增殖[J]. 应用化学, 2018, 35(4): 420-425.
[9]	刘长辉,文瑞明,贺淼,易先文,叶晓琴,方磊. 新型紫罗兰酮基双查尔酮缩氨基硫脲的合成及抗肿瘤活性[J]. 应用化学, 2017, 34(8): 899-904.
[10]	郭威凤, 许晋芳, 刘锐玲, 赵正保, 郭跃伟. 汉防己甲素衍生物的合成及其生物活性[J]. 应用化学, 2017, 34(7): 789-794.
[11]	马涛, 杨金会, 牛明杰, 叶子平, 李方辉. 3种香叶基取代黄烷酮的合成及抗肿瘤活性[J]. 应用化学, 2017, 34(10): 1140-1149.
[12]	谭绪霞, 李世宁, 赵杰, 毛伸, 毛龙飞, 徐桂清. 新型1,1-二氧代-4H-苯并[1,2,4]-噻二嗪类衍生物的合成及其抗肿瘤活性[J]. 应用化学, 2016, 33(9): 1067-1072.
[13]	任丽磊, 彭晓霞, 赵秀丽, 祝红梅. 5-氟尿嘧啶修饰卟啉的合成及抗肿瘤活性[J]. 应用化学, 2016, 33(12): 1415-1419.
[14]	谢玉锁, 高留州, 闫强, 吴书敏, 倪礼礼, 刘英杰, 黄文龙, 胡国强. 氟喹诺酮C-3均三唑硫醚酮缩氨基硫脲衍生物的合成及抗肿瘤活性[J]. 应用化学, 2016, 33(1): 25-31.
[15]	谢玉锁, 高留州, 闫强, 吴书敏, 倪礼礼, 刘英杰, 黄文龙, 胡国强. 氟喹诺酮C-3均三唑硫醚酮缩氨基硫脲衍生物的合成及抗肿瘤活性[J]. 应用化学, 2016, 33(1): 0-0.