新型3,3'-((4-氯-2H-硫色烯-3-基)亚甲基)双(1H-吲哚)类拓扑异构酶Ⅱ抑制剂的合成及抗肿瘤活性研究

doi:10.6023/cjoc202311023

摘要/Abstract

对已知具有生物活性结构的基团进行对接拼合, 设计合成了含双吲哚、苯并噻喃结构的3,3'-((4-氯-2H-硫色烯-3-基)亚甲基)双(1H-吲哚)类化合物. 进行了目标化合物对6株肿瘤细胞的抗肿瘤实验, 结果表明3,3'-((4-氯-2H-硫色烯-3-基)亚甲基)双(5-甲氧基-1H-吲哚)(5b)、3,3'-((4-氯-7-甲基-2H-硫色烯-3-基)亚甲基)双(5-甲基-1H-吲哚)(5f)和3,3'-((4-氯-7-甲基-2H-硫色烯-3-基)亚甲基)双(N-甲基-2-甲基-吲哚)(5g)对肿瘤细胞抗增殖活性较好. 拓扑异构酶抑制实验结果表明, 化合物5b、3,3'-((4-氯-2H-硫色烯-3-基)亚甲基)双(6-氰基-1H-吲哚)(5c)、5f和5g对DNA拓扑异构酶II有选择性抑制活性, 其它化合物对DNA拓扑异构酶II表现出不同程度抑制活性. 分子对接研究结果表明, 化合物5b和5g与DNA拓扑异构酶II产生了较为稳定的结合, 具有潜在的抗肿瘤药物研究价值.

关键词: 双吲哚, 抗肿瘤, DNA拓扑异构酶II, 分子对接

A series of 3,3'-((4-chloro-2H-thiochromen-3-yl)methylene)bis(1H-indole) analogues containing bisindole and benzothiopyran structures were designed and synthesized by docking and splicing groups with known bioactive structures. Antitumor assay against six tumor cell lines of the target compounds were screened and the results indicate that 3,3'-(4-chloro- 2H-thioene-3-yl)methylene)bis(5-methoxy-1H-indole) (5b), 3,3'-(4-chloro-7-methyl-2H-thioene-3-yl)methylene)bis(5-methyl- 1H-indole) (5f), and 3,3'-(4-chloro-7-methyl-2H-thioene-3-yl)methylene)bis(N-methyl-2-methylindole) (5g) showed good anti- proliferative activity against tumor cells. The results of topoisomerase inhibition assay showed that compounds 5b, 3,3'-(4-chloro-2H-thioene-3-yl)methylene)bis(6-cyano-1H-indole) (5c), 5f and 5g showed selective inhibitory activity against DNA topoisomerase II, while other compounds showed different levels of DNA topoisomerase II inhibition activity. The results of molecular docking studies indicated that compounds 5b and 5g had stable binding with DNA topoisomerase II, which had potential research value for antitumor drugs.

Key words: bisindole, antitumor, DNA topoisomerase II, molecular docking

引用此文

梁国超, 董婷婷, 纪海莹, 王春艳, 宋亚丽, 张伟. 新型3,3'-((4-氯-2H-硫色烯-3-基)亚甲基)双(1H-吲哚)类拓扑异构酶Ⅱ抑制剂的合成及抗肿瘤活性研究[J]. 有机化学, 2024, 44(6): 1949-1956.

Guochao Liang, Tingting Dong, Haiying Ji, Chunyan Wang, Yali Song, Wei Zhang. Synthesis and Antitumor Activity of Novel 3,3'-((4-Chloro-2H-thiochromen-3-yl)methylene)bis(1H-indole)-Like Topoisomerase II Inhibitors[J]. Chinese Journal of Organic Chemistry, 2024, 44(6): 1949-1956.

导出引用 EndNote|Reference Manager|ProCite|BibTeX|RefWorks

分享此文

H-硫色烯-3-基)亚甲基)双(1H-吲哚)类拓扑异构酶Ⅱ抑制剂的合成及抗肿瘤活性研究”的文章，特向您推荐。请打开下面的网址：https://sioc-journal.cn/Jwk_yjhx/CN/abstract/abstract350658.shtml' name="neirong"> H-硫色烯-3-基)亚甲基)双(1H-吲哚)类拓扑异构酶Ⅱ抑制剂的合成及抗肿瘤活性研究'>

()

图/表 6

图1. 双吲哚类化合物

Figure 1. Bisindole compounds

图式1. 不同位置取代双吲哚类化合物

Scheme 1. Bisindoles substituted at different positions

图式2. 化合物5a~5m的合成路线

Scheme 2. Synthesis of compounds 5a~5m Reagents and conditions: (a) (i) 3-chloropropionic acid, KOH, H2O, 90 ℃; (ii) 6 mol/L HCl aqueous solution; (b) conc. H2SO4; (c) POCl3, DMF, 50 ℃; (d) TsOH-H2O, substituted indole, EtOH, 80 ℃.

Compd.	IC₅₀/(μmol•L^–1)
Compd.	HeLa	H446	U-937	MCF-7	SK-OV-3	HT-29
5a	16.5±1.2	17.6±3.2	12.7±1.1	17.7±2.8	18.6±2.1	19.8±1.9
5b	14.5±2.2	8.6±1.4	10.3±1.9	14.2±1.7	16.8±1.9	14.1±3.4
5c	22.4±2.7	18.8±2.0	11.9±2.4	10.5±2.2	15.4±1.6	12.2±2.3
5d	38.4±3.3	65.6±3.6	72.7±4.1	47.5±2.5	66.6±2.4	72.6±3.9
5e	20.5±1.5	28.9±1.4	21.4±2.1	65.1±4.2	41.5±2.7	25.3±3.2
5f	8.7±1.2	8.8±2.1	14.3±3.1	14.9±1.7	13.3±2.7	21.1±1.6
5g	10.6±2.3	12.8±1.4	10.5±1.7	7.4±1.8	14.7±3.6	12.7±2.3
5h	66.7±2.6	32.5±1.7	45.7±4.5	34.6±2.2	64.3±3.9	22.6±2.4
5i	45.2±3.6	37.8±3.1	35.2±2.8	29.5±3.3	56.2±4.2	36.6±3.6
5j	65.7±2.9	50.4±3.6	45.8±5.5	63.4±4.6	45.6±4.5	67.2±4.4
5k	36.4±6.3	62.1±6.4	76.8±4.8	68.4±2.2	45.7±3.1	53.1±3.7
5l	19.6±2.3	20.6±1.9	35.7±3.4	58.2±4.6	64.2±2.9	60.7±3.6
5m	72.5±4.3	48.4±3.4	32.4±2.1	54.0±5.2	62.4±3.2	43.2±4.2
VP-16	8.6±1.4	9.1±0.4	8.2±1.5	8.4±0.6	9.8±1.5	7.2±1.1
CPT	7.4±1.5	8.7±1.3	10.4±1.5	7.8±1.4	8.5±1.2	7.7±1.2

表1. 化合物5a~5m对HeLa、H446、U-937、MCF-7、SK-OV-3和HT-29肿瘤细胞的抑制活性

Table 1. Inhibitory activity of compounds 5a~5m against HeLa, H446, U-937, MCF-7, SK-OV-3 and HT-29 tumor cells

图2. 化合物5a~5m对Topo II的抑制活性

Figure 2. Enzymatic inhibitory activities of compounds 5a~5m against Topo II D: pBR 322 DNA; T: pBR 322 DNA+Topo II; V: pBR 322 DNA+Topo II+VP-16; 5a~5m: pBR 322 DNA+Topo II+compounds 5a~5m

图3. 化合物5g和5b与人Topo II (PDB ID: 5GWK)的分子对接研究

Figure 3. Molecular docking studies of compounds 5g and 5b with human Topo II (PDB ID: 5GWK)

参考文献 35

[1]	Azarova, A. M.; Lyu, Y. L.; Lin, C. P.; Tsai, Y. C.; Lau, J. Y.; Wang, J. C.; Liu, L. F. Natl. Acad. Sci. U. S. A. 2007, 104, 11014.
[2]	Deweese, J. E.; Osheroff, N. Nucleic Acids Res. 2009, 37, 738. doi: 10.1093/nar/gkn937 pmid: 19042970
[3]	Haffner, M. C.; Aryee, M. J.; Toubaji, A.; Esopi, D. M.; Albadine, R.; Gurel, B.; Isaacs, W. B.; Bova, G. S.; Liu, W.; Xu, J.; Meeker, A.K.; Netto, G.; De Marzo, A. M.; Nelson, W. G.; Yegnasubramanian, S. Nat. Genet. 2010, 42, 668.
[4]	Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106, 2875. pmid: 16836303
[5]	Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103, 893.
[6]	Ding, S. E.; Dudley, S.; Plummer, S.; Tang, J.; Newton, R. P.; Brenton, A. G. Phytochemistry 2008, 69, 1555. doi: 10.1016/j.phytochem.2008.01.026 pmid: 18342344
[7]	Ahuja, P.; Siddiqui, N. Eur. J. Med. Chem. 2014, 80, 509.
[8]	Zhang, M. Z.; Mulholl, N.; Beattie, D.; Irwin, D.; Gu, Y. C.; Chen, Q.; Yang, G. F.; Clough, J. Eur. J. Med. Chem. 2013, 63, 22.
[9]	Zhang, M. Z.; Chen, Q.; Yang, G. F. Eur. J. Med. Chem. 2015, 89, 421.
[10]	Hu, H. Y.; Wu, J.; Ao, M. T.; Wang, H. R.; Zhou, T. T.; Xue, Y. H.; Qiu, Y. K.; Fang, M. J.; Wu, Z. Chem. Biol. Drug Des. 2016, 88, 766.
[11]	Hu, H. Y.; Yu, X. D.; Wang, F.; Lin, C. R.; Zeng, J. Z.; Qiu, Y. K.; Fang, M. J.; Wu, Z. Molecules 2016, 21, 1.
[12]	Hu, H. Y.; Lin, C. R.; Ao, M. T.; Ji, Y. F.; Tang, B. W.; Zhou, X. X.; Fang, M. J.; Zeng, J. Z.; Wu, Z. RSC Adv. 2017, 7, 51640
[13]	Jiang, B.; Gu, X. H. Bioorg. Med. Chem. 2000, 8, 36
[14]	Brana, M. F.; Gradillas, A.; Ovalles, A. G.; Lopez, B.; Acero, N.; Llinares, F.; Munoz Mingarro, D. Bioorg. Med. Chem. 2006, 14, 9
[15]	Shintani, A.; Toume, K.; Rifai, Y.; Arai, M. A.; Ishibashi, M. J. Nat. Prod. 2010, 73, 1711 doi: 10.1021/np1002687 pmid: 20839811
[16]	Song, Y. L.; Dong, Y. F.; Yang, T.; Zhang, C. C.; Su, L. M.; Huang, X.; Zhang, D. N.; Yang, G. L.; Liu, Y. X. Bioorg. Med. Chem. 2013, 21, 7624
[17]	Zhang, W. J.; Liu, Z.; Li, S. M.; Yang, T. T.; Zhang, Q. B.; Ma, L.; Tian, X. P.; Zhang, H. B.; Huang, C. G.; Zhang, S.; Ju, J. J.; Shen, Y. M.; Zhang, C. S. Org. Lett. 2012, 14, 3364
[18]	Liu, Y. P.; Zhao, Y. L.; Feng, T. Cheng, G. G.; Zhang, B. H.; Li, Y.; Cai, X. H.; Luo, X. D. J. Nat. Prod. 2013, 76, 2322
[19]	Gong, Y.; Firestone, G. L.; Bjeldanes, L. F. Mol. Pharmacol. 2006, 69, 1320.
[20]	Cho, H. J.; Park, S. Y.; Kim, E. J.; Kim, J. K.; Park, J. H. Y. Mol. Carcinogen. 2011, 50, 100
[21]	Safe, S.; Papineni, S.; Chintharlapalli, S. Cancer. Lett. 2008, 269, 326
[22]	Maciejewska, D.; Rasztawicka, M.; Wolska, I.; Anuszewska, E. Z.; Gruber, B. Eur. J. Med. Chem. 2009, 44, 4136. doi: 10.1016/j.ejmech.2009.05.011 pmid: 19540023
[23]	Chaniyara, R.; Tala, S.; Chen, C. W.; Zang, X.; Kakadiya, R.; Lin, L. F.; Chen, C. H.; Chien, S. I.; Chou, T. C.; Tsai, T. H. J. Med. Chem. 2013, 56, 1544 doi: 10.1021/jm301788a pmid: 23360284
[24]	Chen, C. W.; Chen, Y. F.; Chao, S. H.; Tala, S.; Su, T. L.; Lee, T. C. Mol. Cancer Ther. 2013, 12, B259
[25]	Sun, X. Y.; Feng, S. R.; Dong, J. J.; Feng, J. J.; Liu, Z. M.; Song, Y. L.; Qiao, X. Q. Chin. J. Org. Chem. 2020, 40, 391. (in Chinese)
	(孙晓阳, 冯思冉, 董金娇, 冯佳佳, 刘振明, 宋亚丽, 乔晓强, 有机化学, 2020, 40, 391.) doi: 10.6023/cjoc201907006
[26]	Song, J. L.; Jones, L. M.; Kishore Kumar, G. D.; Conner, E. S.; Bayeh, L.; Chavarria, G. E.; Charlton-Sevcik, A. K.; Chen, S. E.; Chaplin, D. J.; Trawick, M. L.; Pinney, K. G. Bioorg. Med. Chem. Lett. 2013, 23, 2801.
[27]	Wei, P.; Liu, J. J.; Ma, J. J.; Yang, G. L. Mod. Appl. Sci. 2010, 12, 136.
[28]	Liu, Y.; Luo, W.; Sun, L. Drug. Discovery Ther. 2008, 2, 216.
[29]	Fang, B. L.; Ma, Z. Y.; Yang, G. L.; Wang, G.; Tian, Wei.; Li, L. B. Int. J. Chem. 2010, 2, 143.
[30]	Han, X. Y.; Li, S. B.; Liang, G. C.; Song, Y. L. Acta Pharm. Sin. 2017, 52, 113. (in Chinese)
	(韩晓燕, 李生彬, 梁国超, 宋亚丽, 药学学报, 2017, 52, 113.)
[31]	Han, Q.; Pabba, P. K.; Barbosa, J.; Mabon, R.; Healy, J. P.; Gardyan, M. W.; Terranova, K. M.; Brommage, R.; Thompson, A.Y.; Schmidt, J. M.; Wilson, A. G.; Xu, X. L.; Tarverjr, J. E.; Carson, K. G. Bioorg. Med. Chem. Lett. 2016, 26, 1103.
[32]	Wang, D. J.; Hou, Z.; Xu, H.; An, R.; Su, X.; Guo, C. Bioorg. Med. Chem. Lett. 2018, 28, 3574.
[33]	Yin, L. J.; Li, C. Q.; Wu, X. X.; Xu, G. S.; Li, Z. Y.; Shen, Y. M. Chin. J. Org. Chem. 2022, 42, 293. (in Chinese)
	(尹丽君, 李超群, 吴晓霞, 徐广森, 李志颖, 沈月毛, 有机化学, 2022, 42, 293.) doi: 10.6023/cjoc202105008
[34]	Han, X. Y. M.S. Thesis, Hebei University, Baoding, 2017. (in Chinese)
	(韩晓燕, 硕士论文, 河北大学, 保定, 2017.)
[35]	Mosmann, T. J. Immunol. Methods 1983, 65, 55. doi: 10.1016/0022-1759(83)90303-4 pmid: 6606682