二氢噻吩并吡啶-查尔酮衍生物的合成及其体外抗肿瘤活性研究

doi:10.6023/cjoc202101014

摘要/Abstract

以2-噻吩乙胺与自制的查尔酮酸进行酰化反应得到酰胺类中间体5a~5j, 经Bischer-Napieralski环合反应合成了10个未见报道的二氢噻吩并吡啶-查尔酮衍生物6a~6j, 再经去氢反应获得2个噻吩并吡啶-查尔酮衍生物7a和7b. 通过噻唑蓝(MTT)法对11种细胞进行体外抗癌活性及安全性测试. 结果表明, 化合物6a (p-F)、6d (o-Br)和6h (m-OCH₃)对HeLa、SGC-7901细胞的抗癌活性优于紫杉醇. 当短时间处理(<4 h)时, 6j (3,4,5-OCH₃)在不影响正常细胞MCF-10A的情况下对癌细胞MCF-7显示强效抗癌效果, 值得进一步研究和开发.

关键词: 二氢噻吩并吡啶-查尔酮衍生物, 抗癌活性, 选择性, 药物摄取能力

The amide intermediates 5a~5j were prepared by acylation, which used 2-thiopheneethylamine and several self-synthetic chalcone acids as starting materials. Then ten dihydrothiophenopyridine-chalcone derivatives 6a~6j which haven't been reported before were synthesized by Bischer-Napieralski cyclization reaction from the intermediates. In addition, two new thiophenopyridine-chalconone derivatives 7a and 7b were obtained by further dehydrogenation. The anti-cancer activity and safety in vitro of 11 kinds of cells were evaluated by methyl thiazolyl tetrazolium (MTT) assay. The results indicated that the compounds 6a (p-F), 6d (o-Br) and 6h (m-OCH₃) exerted better anticancer activity against HeLa and SGC-7901 cells than taxol. When treating cells for a short time (<4 h), 6j (3,4,5-(OCH₃)₃) showed strong anticancer activity against MCF-7 cancer cell but displayed little toxicity on normal breast cell MCF-10A. Hence, 6j deserves further research and exploitation.

Key words: dihydrothiophenopyridine-chalcone derivatives, anticancer activity, selectivity, drug uptake capacity

引用此文

刘新, 许润梅, 王淋, 刘雅雪, 陈志豪, 秦巍, 田玉顺. 二氢噻吩并吡啶-查尔酮衍生物的合成及其体外抗肿瘤活性研究[J]. 有机化学, 2021, 41(9): 3550-3559.

Xin Liu, Runmei Xu, Lin Wang, Yaxue Liu, Zhihao Chen, Wei Qin, Yushun Tian. Synthesis and Evaluation in vitro of Dihydrothiophenopyridine-Chalcone Derivatives as Anticancer Activity Agents[J]. Chinese Journal of Organic Chemistry, 2021, 41(9): 3550-3559.

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参考文献 32

[1]	Khalifa, S. A. M.; Elias, N.; Farag, M. A.; Chen, L.; Saeed, A.; Hegazy, M. F.; Moustafa, M. S.; Abd, E. A.; Al-Mousawi, S. M.; Musharraf, S. G.; Chang, F. R.; Iwasaki, A.; Suenaga, K.; Alajlani, M.; Göransson, U.; El-Seedi, H. R. Mar. Drugs 2019, 17, 491. doi: 10.3390/md17090491
[2]	Fujita, M.; Nakao, Y.; Matsunaga, S.; Seiki, M.; Itoh, Y.; Yamashita, J.; Van Soest, R. W. M.; Fusetani, N. J. Am. Chem. Soc. 2003, 125, 1570.
[3]	Bickmeyer, U.; Thoms, S.; Koch, F.; Mukagatare, L. P.; Silalahi, R.; Sartoris, F. J. PLoS One 2019, 14, e0213771. doi: 10.1371/journal.pone.0213771
[4]	Iwata, T.; Otsuka, S.; Tsubokura, K.; Kurbangalieva, A.; Arai, D.; Fukase, K.; Nakao, Y.; Tanaka, K. Chem.-Eur. J. 2016, 22: 14707.
[5]	Ma, Y.; Nam, S.; Jove, R.; Yakushijin, K.; Horne, D. Bioorg. Med. Chem. Lett. 2010, 20, 84.
[6]	Srivastava, B. K.; Solanki, M.; Mishra, B.; Soni, R.; Jayadev, S.; Valani, D.; Jain, M.; Patel, P. R. Bioorg. Med. Chem. Lett. 2007, 17, 1924. pmid: 17276057
[7]	Tang, J.; Lackey, K. E.; Dickerson, S. H. Bioorg. Med. Chem. Lett. 2013, 23, 66. doi: 10.1016/j.bmcl.2012.11.020 pmid: 23218715
[8]	Liu, H.; Li, Y.; Wang, X. Y.; Wang, B.; He, H. Y.; Liu, J. Y.; Xiang, M. L.; He, J.; Wu, X. H.; Yang, L. Bioorg. Med. Chem. Lett. 2013, 23, 2349. doi: 10.1016/j.bmcl.2013.02.059
[9]	Zhou, S. B; Duan, Y. N.; Wang, J.; Zhang, J.; Sun, H. F; Jiang, H. W; Gu, Z. N; Tong, J. H; Li, J. Y; Li, J.; Liu, H. Eur. J. Med. Chem. 2017, 140, 448. doi: 10.1016/j.ejmech.2017.09.012
[10]	Kühn, F. J. P.; Kuhn, C.; Lückhoff, A. J. Biol. Chem. 2019, 16, 4102.
[11]	Wei, K. R.; Peng, X. B.; Liang, Z. H.; Cen, H. S. China Cancer 2015, 24, 621. (in Chinese).
	( 魏矿荣, 彭侠彪, 梁智恒, 岑惠珊, 中国肿瘤, 2015, 24, 621.)
[12]	Zeng, X. X.; Zheng, R. L.; Zhou, T.; He, H. Y.; Liu, J. Y.; Zheng, Y.; Tong, A. P.; Xiang, M. L.; Song, X. R.; Yang, S. Y.; Yu, L. T.; Wei, Y. Q.; Zhao, Y. L.; Yang, L. Bioorg. Med. Chem. Lett. 2010, 20, 6282. doi: 10.1016/j.bmcl.2010.08.088
[13]	Tian, L.; Wu, G. R.; Wang, Y. Northwest Pharm. J. 2007, 22, 218. (in Chinese).
	( 田兰, 吴桂荣, 王岩, 西北药学杂志, 2007, 22, 218.)
[14]	Wang, Y. H.; Bai, H.; Dou, D. Q.; Pei, Y. P.; Chen, Y. J.; Li, W.; Kazuo, K.; Xing, S. R; Tamots, N. Northwest Pharm. J. 2004, 19, 253. (in Chinese).
	( 王英华, 白虹, 窦德强, 裴玉萍, 陈英杰, 李巍, 小池一男, 邢世瑞, 二阶堂保, 西北药学杂志, 2004, 19, 253.)
[15]	Jandial, D. D.; Krill, L. S.; Chen, L.; Wu, C.; Ke, Y.; Xie, J.; Hoang, B. H.; Zi, X. Molecules 2017, 22, 462. doi: 10.3390/molecules22030462
[16]	Kurt, B. Z.; Kandas, N. O.; Dag, A.; Sonmez, F.; Kucukislamoglu, M. Arab. J. Chem. 2020, 13, 1120. doi: 10.1016/j.arabjc.2017.10.001
[17]	Sheng, Q. E.; Zhao, W. Q.; Zeng, M.; Xie, Z. B.; Xia, Y. P.; Cui, D. M. Chin. J. Org. Chem. 2019, 39, 703. (in Chinese). doi: 10.6023/cjoc201808037
	( 盛琦威, 赵婉秋, 曾明, 谢中袍, 夏雅平, 崔冬梅, 有机化学, 2019, 39, 703.)
[18]	Roussaki, M.; Hall, B.; Lima, S. C.; Da, S. A. C.; Wilkinson, S.; Detsi, A. Bioorg. Med. Chem. Lett. 2013, 23, 6436. doi: 10.1016/j.bmcl.2013.09.047 pmid: 24119553
[19]	Dong, L. R.; Hu, D. Y.; Wu, Z. X.; Chen, J. X.; Song, B. A. Chin. Chem. Lett. 2017, 28, 1566. doi: 10.1016/j.cclet.2017.03.013
[20]	Abdullah, M. I.; Mahmood, A.; Madni, M.; Masood, S.; Kashif, M. Bioorg. Chem. 2014, 54, 31. doi: 10.1016/j.bioorg.2014.03.006
[21]	Anuradha, V.; Pullela, V.; Srinivas, R.; Ranga, R. K.; Manjulatha, M. G.; Purohit, J.; Adhusudana, R. Bioorg. Med. Chem. 2006, 14, 6820. doi: 10.1016/j.bmc.2006.06.048
[22]	Zhao, L.; Jin, H.; Sun, L.; Piao, H.; Quan, Z. Bioorg. Med. Chem. Lett. 2005, 15, 5027. doi: 10.1016/j.bmcl.2005.08.039
[23]	Zhao, L. J.; Shi, Y.; Liu, W.; Lin, X. M.; Sun, T. M.; Li, Y. L. Chin. J. Med. Chem. 2010, 20, 163. (in Chinese).
	( 赵乐晶, 石玉, 刘巍, 林晓明, 孙铁民, 李祎亮, 中国药物化学杂志, 2010, 20, 163.)
[24]	Tamayo, N. A.; Bo, Y.; Gore, V.; Ma, V.; Nishimura, N.; Tang, P.; Deng, H.; Klionsky, L.; Lehto, S. G.; Wang, W.; Youngblood, B.; Chen, J.; Correll, T. L.; Bartberger, M. D.; Gavva, N. R.; Norman, M. H. J. Med. Chem. 2012, 55, 1594.
[25]	Shumaila, A. M. A.; Puranik, V. G.; Kusurkar, R. S. Tetrahedron 2011, 67, 936. doi: 10.1016/j.tet.2010.12.003
[26]	Yan, Y. K.; Xu, Q.; Gao, Y.; Liu, H.; Tang, X. R. Chin. J. Org. Chem. 2018, 38, 1763. (in Chinese). doi: 10.6023/cjoc201712027
	( 严映坤, 徐侨, 高扬, 刘辉, 唐孝荣, 有机化学, 2018, 38, 1763.)
[27]	Zhang, J.; Li, F.; Li, Y.; Guo, Y.; Wang, J.; Zhang, S. Med. Chem. 2014, 10, 277. doi: 10.2174/157340641003140304144930
[28]	Liu, Y. N.; Wang, J. J.; Ji, Y. T.; Zhao, G. D.; Tang, L. Q.; Zhang, C. M.; Guo, X. L.; Liu, Z. P. J. Med. Chem. 2016, 59, 5341. doi: 10.1021/acs.jmedchem.6b00071
[29]	Farooq, S.; Ngaini, Z.; Mortadza, N. A. Bull. Korean Chem. Soc. 2020, 41, 920.
[30]	de Souza, A. C. A.; Mori, M.; Sens, L.; Rocha, R. F.; Tizziani, T.; de Souza, L. F. S.; Domeneghini Chiaradia-Delatorre, L.; Botta, M.; Nunes, R. J.; Terenzi, H.; Menegatti, A. C. O. Bioorg. Med. Chem. Lett. 2007, 30, 127350. doi: 10.1016/j.bmcl.2020.127350
[31]	Jakovljevic, K.; Joksovic, M.; Matić, I. Z.; Petrovic, N.; Stanojkovic, T.; Sladić, D.; Vujcic, M.; Janovic, B.; Joksovic, L.; Trifunovic, S.; Marković, V. Med. Chem. Comm. 2018, 9, 1682.
[32]	Parveen, Z.; Brunhofer, G.; Jabeen, I.; Erker, T.; Chiba, P.; Ecker, G. F. Bioorg. Med. Chem. Lett. 2014, 22, 2314.

Compd.	R	IC₅₀/(µmol•L^–1)
Compd.	R	BEL-7402	HepG2	HCT116	A549	MGC-803	SGC-7901	AGS	MCF-7	MCF-10A	HeLa	L-02
3a	p-F	31.7±5.4	>100	10.7±2.2	>100	18.9±2.1	22.0±1.3	22.7±7.8	40.6±9.2	32.8±2.8	39.1±12.1	21.2±5.7
3b	p-Cl	>100	>100	>100	>100	>100	>100	>100	>100	>100	>100	>100
3c	p-H	14.3±3.4	>100	21.0±0.5	>100	>100	>100	32.3±1.4	24.1±0.4	47.4±4.6	35.3±2.3	27.1±1.6
3d	o-Br	25.8±3.3	94.3±5.1	8.63±2.1	>100	15.4±6.1	26.6±4.6	22.8±7.3	45.1±5.7	37.2±6.9	69.5±8.8	23.4±2.8
3e	m-Br	5.9±0.03	11.7±4.7	3.0±2.0	20.2±4.3	5.3±0.8	3.2±0.8	5.3±3.5	13.6±2.3	8.2±2.3	23.5±8.8	5.3±0.3
3f	p-Br	10.3±0.1	35.5±13.7	3.5±1.9	57.2±4.5	9.9±1.2	3.3±1.9	12.8±3.0	17.2±4.5	16.1±2.7	15.0±4.9	11.4±3.4
3g	p-CH₃	16.0±2.5	42.0±3.2	8.0±1.9	50.8±3.0	15.1±1.0	12.5±1.5	24.7±7.0	27.4±3.9	28.9±5.5	36.3±7.9	15.6±1.8
3h	m-OCH₃	23.6±2.7	44.5±15.4	7.2±0.9	>100	15.6±0.8	11.7±1.1	36.7±10.2	28.0±3.9	28.8±7.4	55.4±8.9	18.8±2.1
3i	p-OCH₃	12.3±3.1	89.6±0.4	6.4±3.2	>100	8.5±0.8	10.7±2.2	16.9±1.5	>100	51.1±5.7	42.6±8.0	7.5±1.7
3j	3,4,5-(OCH₃)₃	8.0±1.4	>100	>100	>100	11.0±1.4	>100	11.3±3.4	21.5±4.3	38.8±11.8	39.4±1.2	5.8±2.6
Taxol		0.09±0.02	0.94±0.03	0.03±0.01	0.44±0.02	0.06±0.01	>100	0.02±0.01	0.08±0.01	0.18±0.02	13.0±0.4	>100

Compd.	R	IC₅₀/(µmol•L^–1)
Compd.	R	BEL-7402	HepG2	HCT116	A549	MGC-803	SGC-7901	AGS	MCF-7	MCF-10A	HeLa	L-02
3a	p-F	31.7±5.4	>100	10.7±2.2	>100	18.9±2.1	22.0±1.3	22.7±7.8	40.6±9.2	32.8±2.8	39.1±12.1	21.2±5.7
3b	p-Cl	>100	>100	>100	>100	>100	>100	>100	>100	>100	>100	>100
3c	p-H	14.3±3.4	>100	21.0±0.5	>100	>100	>100	32.3±1.4	24.1±0.4	47.4±4.6	35.3±2.3	27.1±1.6
3d	o-Br	25.8±3.3	94.3±5.1	8.63±2.1	>100	15.4±6.1	26.6±4.6	22.8±7.3	45.1±5.7	37.2±6.9	69.5±8.8	23.4±2.8
3e	m-Br	5.9±0.03	11.7±4.7	3.0±2.0	20.2±4.3	5.3±0.8	3.2±0.8	5.3±3.5	13.6±2.3	8.2±2.3	23.5±8.8	5.3±0.3
3f	p-Br	10.3±0.1	35.5±13.7	3.5±1.9	57.2±4.5	9.9±1.2	3.3±1.9	12.8±3.0	17.2±4.5	16.1±2.7	15.0±4.9	11.4±3.4
3g	p-CH₃	16.0±2.5	42.0±3.2	8.0±1.9	50.8±3.0	15.1±1.0	12.5±1.5	24.7±7.0	27.4±3.9	28.9±5.5	36.3±7.9	15.6±1.8
3h	m-OCH₃	23.6±2.7	44.5±15.4	7.2±0.9	>100	15.6±0.8	11.7±1.1	36.7±10.2	28.0±3.9	28.8±7.4	55.4±8.9	18.8±2.1
3i	p-OCH₃	12.3±3.1	89.6±0.4	6.4±3.2	>100	8.5±0.8	10.7±2.2	16.9±1.5	>100	51.1±5.7	42.6±8.0	7.5±1.7
3j	3,4,5-(OCH₃)₃	8.0±1.4	>100	>100	>100	11.0±1.4	>100	11.3±3.4	21.5±4.3	38.8±11.8	39.4±1.2	5.8±2.6
Taxol		0.09±0.02	0.94±0.03	0.03±0.01	0.44±0.02	0.06±0.01	>100	0.02±0.01	0.08±0.01	0.18±0.02	13.0±0.4	>100

Compd.	R	IC₅₀/(µmol•L^–1)
Compd.	R	BEL-7402	HepG2	HCT116	A549	MGC-803	SGC-7901	AGS	MCF-7	MCF-10A	HeLa	L-02
6a	p-F	6.0±0.2	17.8±2.6	7.6±0.5	23.6±4.9	6.6±1.1	6.0±0.3	8.3±2.6	9.0±3.0	8.5±2.8	10.5±2.6	5.6±1.6
6b	p-Cl	11.0±0.4	>100	10.1±4.1	16.5±2.6	13.8±4.0	>100	11.4±1.4	17.8±0.7	13.7±5.0	28.9±11.3	15.7±1.1
6c	p-H	8.7±1.0	>100	11.8±2.8	18.3±9.7	14.3±2.1	15.1±6.7	10.4±7.6	6.40±1.3	17.9±4.0	19.4±2.3	11.3±2.8
6d	o-Br	3.8±4.8	15.6±0.3	5.1±0.5	20.2±3.5	3.6±1.7	6.7±0.03	5.7±2.5	10.2±1.4	7.6±1.2	10.9±5.6	6.9±1.7
6e	m-Br	5.9±2.9	54.5±31.2	6.5±2.4	20.7±1.1	14.7±5.1	18.3±1.7	24.3±5.6	14.1±5.7	7.4±2.2	13.9±5.6	7.2±3.2
6f	p-Br	>100	>100	5.2±2.1	>100	15.7±0.4	17.3±6.5	37.0±12.7	>100	>100	46.1±1.6	41.1±2.5
6g	p-CH₃	21.8±3.2	>100	9.3±1.3	26.5±5.1	3.4±2.0	8.2±0.2	28.7±8.2	15.1±3.5	20.3±11.7	15.2±4.0	14.9±6.3
6h	m-OCH₃	5.0±3.7	19.2±2.9	6.1±1.3	15.9±5.7	5.6±0.7	9.0±1.0	5.9±4.6	12.3±4.1	10.5±5.1	7.5±1.2	6.1±5.1
6i	p-OCH₃	24.4±4.9	>100	24.0±3.1	23.5±6.8	8.9±2.4	11.0±0.4	17.7±8.0	24.7±7.8	>100	21.8±1.5	11.0±0.7
6j	3,4,5-(OCH₃)₃	6.1±1.3	>100	4.9±1.7	10.9±9.2	6.4±0.5	>100	1.3±0.1	15.0±5.0	16.8±4.3	18.5±9.7	8.2±2.0
7a	p-F	4.5±0.1	>100	17.3±3.2	36.2±2.8	12.3±0.9	24.1±6.4	14.5±3.5	6.5±1.6	27.6±3.6	24.6±4.5	10.7±5.9
7b	p-Cl	62.9±1.0	>100	21.0±0.5	>100	>100	75.4±11.8	48.9±0.4	56.4±10.3	>100	>100	32.5±0.6
Taxol		0.09±0.02	0.94±0.03	0.03±0.01	0.44±0.02	0.06±0.01	>100	0.02±0.01	0.08±0.01	0.18±0.02	13.0±0.4	>100

Compd.	R	IC₅₀/(µmol•L^–1)
Compd.	R	BEL-7402	HepG2	HCT116	A549	MGC-803	SGC-7901	AGS	MCF-7	MCF-10A	HeLa	L-02
6a	p-F	6.0±0.2	17.8±2.6	7.6±0.5	23.6±4.9	6.6±1.1	6.0±0.3	8.3±2.6	9.0±3.0	8.5±2.8	10.5±2.6	5.6±1.6
6b	p-Cl	11.0±0.4	>100	10.1±4.1	16.5±2.6	13.8±4.0	>100	11.4±1.4	17.8±0.7	13.7±5.0	28.9±11.3	15.7±1.1
6c	p-H	8.7±1.0	>100	11.8±2.8	18.3±9.7	14.3±2.1	15.1±6.7	10.4±7.6	6.40±1.3	17.9±4.0	19.4±2.3	11.3±2.8
6d	o-Br	3.8±4.8	15.6±0.3	5.1±0.5	20.2±3.5	3.6±1.7	6.7±0.03	5.7±2.5	10.2±1.4	7.6±1.2	10.9±5.6	6.9±1.7
6e	m-Br	5.9±2.9	54.5±31.2	6.5±2.4	20.7±1.1	14.7±5.1	18.3±1.7	24.3±5.6	14.1±5.7	7.4±2.2	13.9±5.6	7.2±3.2
6f	p-Br	>100	>100	5.2±2.1	>100	15.7±0.4	17.3±6.5	37.0±12.7	>100	>100	46.1±1.6	41.1±2.5
6g	p-CH₃	21.8±3.2	>100	9.3±1.3	26.5±5.1	3.4±2.0	8.2±0.2	28.7±8.2	15.1±3.5	20.3±11.7	15.2±4.0	14.9±6.3
6h	m-OCH₃	5.0±3.7	19.2±2.9	6.1±1.3	15.9±5.7	5.6±0.7	9.0±1.0	5.9±4.6	12.3±4.1	10.5±5.1	7.5±1.2	6.1±5.1
6i	p-OCH₃	24.4±4.9	>100	24.0±3.1	23.5±6.8	8.9±2.4	11.0±0.4	17.7±8.0	24.7±7.8	>100	21.8±1.5	11.0±0.7
6j	3,4,5-(OCH₃)₃	6.1±1.3	>100	4.9±1.7	10.9±9.2	6.4±0.5	>100	1.3±0.1	15.0±5.0	16.8±4.3	18.5±9.7	8.2±2.0
7a	p-F	4.5±0.1	>100	17.3±3.2	36.2±2.8	12.3±0.9	24.1±6.4	14.5±3.5	6.5±1.6	27.6±3.6	24.6±4.5	10.7±5.9
7b	p-Cl	62.9±1.0	>100	21.0±0.5	>100	>100	75.4±11.8	48.9±0.4	56.4±10.3	>100	>100	32.5±0.6
Taxol		0.09±0.02	0.94±0.03	0.03±0.01	0.44±0.02	0.06±0.01	>100	0.02±0.01	0.08±0.01	0.18±0.02	13.0±0.4	>100

Compd.	R	m.p./℃	Yield/%
3a	p-H	212~213	61.8
3b	p-F	255~256	79.7
3c	p-Cl	259~260	95.3
3d	o-Br	232~233	83.9
3e	m-Br	206~207	74.7
3f	p-Br	246~247	77.3
3g	p-CH₃	242~243	81.9
3h	m-OCH₃	101~102	66.3
3i	p-OCH₃	224~226	84.6
3j	3,4,5-(OCH₃)₃	223~224	61.7