含香豆素的吡咯并[2,3-d]嘧啶衍生物的合成及生物活性研究

doi:10.6023/cjoc202301028

摘要/Abstract

为了寻找结构新颖、活性较好的抗肿瘤化合物, 设计并合成了一系列新型的含香豆素的吡咯并[2,3-d]嘧啶衍生物, 并用核磁共振波谱(NMR)和高分辨质谱(HRMS)等方法对化合物结构进行表征. 采用四甲基偶氮唑盐(MTT)法测定了目标化合物对大鼠胶质瘤细胞(C6)、人黑色素瘤细胞(A375)和人口腔鳞癌细胞(FaDu)的抑制活性. 结果显示7-[7-(2-氟苯基)-5-(4-甲氧基苯基)-7H-吡咯并[2,3-d]嘧啶-4-氧基]-4-甲基香豆素(II₁)、7-[7-(2-氟苯基)-5-(4-氟苯基)-7H-吡咯并[2,3-d]嘧啶-4-氧基]-4-甲基香豆素(II₄)、7-[7-(3-氟苯基)-5-(4-甲氧基苯基)-7H-吡咯并[2,3-d]嘧啶-4-氧基]-4-甲基香豆素(III₁)、7-[7-(3-氟苯基)-5-(4-氯苯基)-7H-吡咯并[2,3-d]嘧啶-4-氧基]-4-甲基香豆素(III₃)和7-[7-(3-氟苯基)-5-(4-氟苯基)-7H-吡咯并[2,3-d]嘧啶-4-氧基]-4-甲基香豆素(III₄)对C6细胞具有较好的抑制活性, 优于阳性对照药Imatinib, 其中化合物II₄的抑制活性最好, IC₅₀为9.60 μmol/L; 化合物I₂对FaDu细胞抑制活性最好, IC₅₀为38.61 μmol/L, 优于阳性对照药顺铂.

关键词: 香豆素, 合成, 抗肿瘤

In order to search for new structural anti-tumor drugs, a series of novel pyrrolo[2,3-d]pyrimidine derivatives containing coumarin were synthesized and evaluated for their inhibitory activities against rat glioma cell (C6), human melanoma cell (A375) and oral squamous cell (FaDu) by using methyl thiazolyl tetrazolium (MTT) assay. These chemical structures were well characterized by nuclear magnetic resonance (NMR) and high-resolution mass spectra (HRMS) spectroscopic methods. 7-[7-(2-Fluorobenzyl)-5-(4-methoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-4-methylchromen-2-one (II₁), 7-[7-(2-fluo- robenzyl)-5-(4-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-4-methyl-chromen-2-one (II₄), 7-[7-(3-fluorobenzyl)-5-(4- methoxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-4-methyl-chromen-2-one (III₁), 7-[5-(4-chlorophenyl)-7-(3-fluoroben- zyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-4-methyl-chromen-2-one (III₃) and 7-[7-(3-fluorobenzyl)-5-(4-fluorophenyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yloxy]-4-methyl-chromen-2-one (III₄) had better inhibitory activity against C6 cells than imatinib, compound II₄ showed the most potent inhibitory activity against C6 cells with the IC₅₀ values of 9.60 μmol/L. Compounds I₂ had better inhibitory activity against FaDu cells than cisplatin, IC₅₀ was 38.61μmol/L.

Key words: coumarin, synthesis, anticancer

引用此文

曹瑞霞, 贾玉萍. 含香豆素的吡咯并[2,3-d]嘧啶衍生物的合成及生物活性研究[J]. 有机化学, 2023, 43(9): 3304-3311.

Ruixia Cao, Yuping Jia. Synthesis and Biological Activity of Novel Pyrrolo[2,3-d]pyrimidine Derivatives Containing Coumarin[J]. Chinese Journal of Organic Chemistry, 2023, 43(9): 3304-3311.

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图/表 4

图1. 化合物A~C的结构式

Figure 1. Chemical structures of compounds A~C

图2. 目标化合物I1~I5、II1~II5和III1~III5分子设计示意图

Figure 2. Design strategy of the target compounds I1~I5, II1~II5 and III1~III5

图式1. 目标化合物I1~I5、II1~II5和III1~III5的合成路线

Scheme 1. Synthetic routes of the target compounds I1~I5, II1~II5 and III1~III5

Compd.	C6	A375	FaDu
I₁	20.77	138.19	187.62
I₂	33.20	121.52	38.61
I₃	19.50	>200	>200
I₄	60.08	175.83	97.7
I₅	176.68	>200	>200
II₁	12.63	>200	>200
II₂	121.84	>200	>200
II₃	21.25	>200	>200
II₄	9.60	>200	>200
II₅	56.56	>200	>200
III₁	12.25	>200	>200
III₂	157.97	>200	>200
III₃	14.73	>200	>200
III₄	14.95	>200	>200
III₅	>200	>200	>200
Imatinib	15.08	36.10	—
Cisplatin	—	—	55.10

表1. 化合物I1~I5、II1~II5和III1~III5对三种肿瘤细胞的体外抗增殖活性[IC50/(mol?L–1)]

Table 1. Anti-cancer activity of the synthetic derivatives I1~I5, II1~II5 and III1~III5 [IC50/(mol?L–1)]

参考文献 24

[1]	Zhang S. Y.; Meng L.; Gao W. Y.; Song N. N.; Jia W.; Duan H. Q. China J. Chin. Mater. Med. 2005, 30, 410. (in Chinese)
	(张韶瑜, 孟林, 高文远, 宋乃宁, 贾伟, 段宏泉, 中国中药杂志, 2005, 30, 410.)
[2]	Beillerot A.; Dominguez J. C.; Kirsch G.; Bagrel D. Bioorg. Med. Chem. Lett. 2008, 18, 1102. doi: 10.1016/j.bmcl.2007.12.004 pmid: 18164200
[3]	Matos M.J.; Teran C.; Perez-Castillo Y.; Uriarte E.; Santana L.; Vina D. J. Med. Chem. 2011, 54, 7127. doi: 10.1021/jm200716y
[4]	Wu L.; Wang X.; Xu W.; Farzaneh F.; Xu R. Curr. Med. Chem. 2009, 16, 4236. doi: 10.2174/092986709789578187
[5]	Ji H.; Tan Y. L.; Gan N. N.; Zhang J.; Li S. N.; Zheng X.; Wang Z. H.; Yi W. Bioorg. Med. Chem. 2021, 29, 115870. doi: 10.1016/j.bmc.2020.115870
[6]	Emami S.; Dadashpour S. Eur. J. Med. Chem. 2015, 102, 611. doi: 10.1016/j.ejmech.2015.08.033
[7]	Li Y. Y; Tang Q.; Xie Y.; He D.; Yang K.; Zheng L. F. Bioorg. Med. Chem. Lett. 2021, 33, 127750. doi: 10.1016/j.bmcl.2020.127750
[8]	Yang K.; Li Y. Y.; Tang Q.; Zheng L. F.; He D. Eur. J. Med. Chem. 2019, 170, 45. doi: S0223-5234(19)30211-9 pmid: 30878831
[9]	Shi L.; Li Z. Q.; Cui X. X.; Zhu T.; Pang X. J.; Li L. H.; Luo D. F.; Liu F. F.; Zhao B. Y.; Long Y.; Zhang S. Y. Chin. J. Org. Chem. 2020, 40, 1598. (in Chinese) doi: 10.6023/cjoc201911028
	(时蕾, 李子秋, 崔鑫鑫, 朱挺, 庞晓静, 李龙辉, 罗德福, 刘方芳, 赵冰玉, 龙跃, 张赛扬, 有机化学, 2020, 40, 1598.) doi: 10.6023/cjoc201911028
[10]	Yuan J. L.; Shi B. Y.; Lu F.; Cao S. L. Chin. J. Synth. Chem. 2011, 19, 149. (in Chinese)
	(袁京莉, 史博颖, 鲁丰, 曹胜利, 合成化学, 2011, 19, 149.)
[11]	Dang Q.; Gomez-Galeno J. E. J. Org. Chem. 2002, 67, 8703.
[12]	Danchev N.; Bijev A.; Yaneva D.; Vladimirova S.; Nikolova I. Arch. Pharm. Chem. Life Sci. 2006, 339, 670. doi: 10.1002/(ISSN)1521-4184
[13]	Gangjee A.; Jain H. D.; Kisliuk R. L. Bioorg. Med. Chem. Lett. 2005, 15, 2225. pmid: 15837298
[14]	Finch R. A.; Revankar G. R.; Chan P. K. Anti-Cancer Drug Des. 1997, 12, 205. doi: 10.1097/00001813-200103000-00005
[15]	Mosaad S.; Mohamed R. K.; Rania H.; Abd E. Med. Chem. Res. 2013, 22, 2244. doi: 10.1007/s00044-012-0217-5
[16]	Ding J.; Liu T.; Zeng C. G.; Li B. Q.; Ai Y.; Zhang X. H.; Zhong H. Chem. Heterocycl. Com. 2022, 58, 438.
[17]	Saito Y.; Yuki H.; Kuratani M.; Hashizume Y.; Takagi S.; Honma T.; Tanaka A.; Shirouzu M.; Mikuni J.; Handa N.; Ogahara I.; Sone A.; Najima Y.; Tomabechi Y.; Wakiyama M.; Uchida N.; Tomizawa-Murasawa M.; Kaneko A.; Tanaka S.; Suzuki N.; Kajita H.; Aoki Y.; Ohara O.; Shultz L. D.; Fukami T.; Goto T.; Taniguchi S.; Yokoyama S.; Ishikawa F. Sci. Transl. Med. 2013, 5, 181.
[18]	Lee J. H.; El-Damasy A. K.; Seo S. H.; Gadhe C. G.; Pae A. N.; Jeong N.; Hong S. S.; Keum G. Bioorg. Med. Chem. 2018, 26, 5596. doi: 10.1016/j.bmc.2018.10.004
[19]	Lu L.; Guo Q. L.; Zhao L. J. Chin. Pharm. Univ. 2017, 48, 377. (in Chinese)
	(陆璐, 郭青龙, 赵丽, 中国药科大学学报, 2017, 48, 377.)
[20]	Kaspersen S. J.; Han J.; Nørsett K. G.; Rydså L.; Kjøbli E.; Bugge S.; Bjørkøy G.; Sundby E.; Hoff B. H. Eur. J. Pharm. Sci. 2014, 59, 69. doi: 10.1016/j.ejps.2014.04.011 pmid: 24769040
[21]	Musumeci F.; Fallacara A. L.; Brullo C.; Grossi G.; Botta L.; Calandro P.; Chiariello M.; Kissova M.; Crespan E.; Maga G.; Schenone S. Eur. J. Med. Chem. 2017, 127, 369. doi: 10.1016/j.ejmech.2016.12.036
[22]	Pudlo J. S.; Nassiri M. R.; Kern E. R.; Wotring L. L.; Drach J. C.; Townsend L. B. J. Med. Chem. 1990, 33, 1984. pmid: 2163454
[23]	Xing Q. Y.; Pei W. W.; Xu R. Q.; Pei J. Basic Organic Chemistry, Higher Education Press, Beijing, 2016, pp. 912-913. (in Chinese)
	(邢其毅, 裴伟伟, 徐瑞秋, 裴坚, 基础有机化学, 高等教育出版社, 北京, 2016, pp. 912-913.)
[24]	Situ Z. Q.; Wu J. Z. Cell Culture, World Book Inc., Xi'an, 2004, pp. 250-252. (in Chinese)
	(司徒镇强, 吴军正, 细胞培养, 世界图书出版社, 西安, 2004, pp. 250-252.)