苦参碱缩氨基脲类化合物的合成及其体外抗肿瘤活性研究
收稿日期: 2022-09-30
修回日期: 2022-12-11
网络出版日期: 2023-01-12
基金资助
国家级大学生创新创业训练计划(202010601021); 广西高校中青年科研基础能力提升(2019KY051); 广西自然科学基金(2018GXNSFAA281200); 桂林市科学研究与技术开发计划(20210227-1)
Synthesis and in Vitro Antitumor Activity of Matrine Semicarbazide Derivatives
Received date: 2022-09-30
Revised date: 2022-12-11
Online published: 2023-01-12
Supported by
National Innovation and Entrepreneurship Training Program for College Students(202010601021); Guangxi Young and Middle-Aged Scientific Research Basic Ability Improvement Project for Colleges and Universities(2019KY051); Natural Science Foundation of Guangxi Province(2018GXNSFAA281200); Project for Science Research and Technology Development of Guilin City(20210227-1)
为了寻找高效低毒的新型抗肿瘤化合物, 设计并合成了一系列新型的苦参碱缩氨基脲类化合物. 采用噻唑蓝(MTT)法测定目标化合物对人肺癌细胞(A549)、人肝癌细胞(HepG2)、人宫颈癌细胞(Hela)、人胃癌细胞(MGC803)细胞株及人正常肝细胞株(L-O2)的细胞毒活性. 结果表明, 大多数衍生物对肿瘤细胞的细胞毒性明显高于母体化合物. 其中14-甲酰基-15-氯-苦参碱缩N-(3-氯苯基)氨基脲(6c)和14-甲酰基-15-氯-苦参碱缩N-(3-硝基苯基)氨基脲(6f)对人肺癌A549细胞株表现出良好的抑制活性, IC50值分别为(11.70±0.25)和(15.61±0.07) μmol/L, 活性优于阳性对照药喜树碱. 同时, 对人胃癌MGC803细胞株IC50值分别为(11.32±1.07)和(9.27±2.03) μmol/L, 并且对人正常肝细胞株(L-O2)表现出较低的细胞毒性. 流式细胞术及线粒体膜电位检测表明, 化合物6f能够剂量依赖性地诱导MGC803细胞凋亡, 并降低线粒体膜电位. 上述研究为苦参碱的结构修饰提供了思路.
庞盼杏 , 宁蓉 , 祝创 , 黄文洁 , 马献力 , 蒋彩娜 , 李芳耀 , 周小群 . 苦参碱缩氨基脲类化合物的合成及其体外抗肿瘤活性研究[J]. 有机化学, 2023 , 43(6) : 2126 -2135 . DOI: 10.6023/cjoc202209040
In order to search for novel antitumor drugs with high efficiency and low toxicity, matrine semicarbazide derivatives were designed and synthesized. The antiproliferative activities of target compounds in four human cancer cell lines of A549 (lung), HepG2 (liver), Hela (epithelial cervical), MGC-803 (gastric) and a human normal cell of L-O2 (liver) were evaluated by methyl thiazolyl tetrazolium (MTT) assay. Biological screening results demonstrated that most of the derivatives exhibited more potent cytotoxicity against tumor cell lines superior to parent compound matrine. Among them, compounds of 14-formyl-15-chloro-matrine N-(3-chlorophenyl) semicarbazide (6c) and 14-formyl-15-chloro-matrine N-(3-nitrophenyl) semicarbazide (6f) displayed better antiproliferative activity with IC50 values of (11.70±0.25) and (15.61±0.07) μmol/L toward A549 cells compared with camptothecin, and with IC50 values of (11.32±1.07) and (9.27±2.03) μmol/L against MGC-803 cells. Moreover, they exhibited lower cytotoxicity against human normal liver cell line L-O2. Flow cytometry and JC-1 mitochondrial membrane potential detection showed that compound 6f could induce apoptosis of MGC803 cells and reduce the mitochondrial membrane potential. It would provide a new idea for the structural modification of matrine.
Key words： matrine; semicarbazide; synthesis; in vitro antitumor activity
| [1] | Bray, F.; Laversanne, M.; Weiderpass, E.; Soerjomataram, I. Cancer 2021, 127, 3029. |
| [2] | Sung, H.; Ferlay, J.; Siegel, R. L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Ca-Cancer J. Clin. 2021, 71, 209. |
| [3] | Alam, O.; Mullick, P.; Verma, S. P.; Gilani, S. J.; Khan, S. A.; Siddiqui, N.; Ahsan, W. Eur. J. Med. Chem. 2010, 45, 2467. |
| [4] | Sriram, D.; Stables, P. J.; Thirumurugan, R.; Induja, S.; Ragavendran, V. J.; Yogeeswari, P. Med. Chem. 2006, 2, 55. |
| [5] | Yogeeswari, P.; Sriram, D.; Veena, V.; Kavya, R.; Rakhra, K.; Ragavendran, J. V.; Mehta, S.; Thirumurugan, R.; Stables, J. P. Biomed. Pharmacother. 2005, 59, 51. |
| [6] | Xu, H.; Su, X.; Liu, X.Q.; Zhang, K. P.; Hou, Z.; Guo, C. Bioorg. Med. Chem. Lett. 2019, 29, 23. |
| [7] | Hania, M. M. E-J. Chem. 2009, 6, 508. |
| [8] | Gopi, C.; Dhanaraju, D. M. Beni-Suef Univ. J. Basic Appl. Sci. 2018, 7, 291. |
| [9] | Chipeleme, A.; Gut, J.; Rosenthal, P. J.; Chibale, K. Bioorg. Med. Chem. 2007, 15, 273. |
| [10] | Queiroz, A. C.; Alves, M. A.; Barreiro, E. J.; Lima, L. M.; Alexandre-Moreira, M. S. Exp. Parasitol. 2019, 201, 57. |
| [11] | Qazi, S. U.; Naz, A.; Hameed, A.; Osra, F. A.; Jalil, S.; Iqbal, J.; Ali Shah, S. A.; Mirza, A. Z. Bioorg. Chem. 2021, 115, 105209. |
| [12] | Liu, Y.-B.; Peng, W.-L.; Yu, L.-J.; Xing, J.-H.; Chen, J.; Xia, X.-J.; Shen, D.-L. Agrochemicals 2010, 49, 407. (in Chinese) |
| [12] | (刘永榜, 彭伟立, 郁林军, 邢家华, 陈杰, 夏旭建, 沈德隆, 农药, 2010, 49, 407.) |
| [13] | Ma, J. J.; Hu, G.; Xie, L. J.; Chen, L.; Xu, B. X.; Gong, P. Chem. Res. Chin. Univ. 2015, 31, 958. |
| [14] | Jia, X. X.; Liu, Q.; Wang, S. Y.; Zeng, B. L.; Du, G. H.; Zhang, C.; Li, Y. Bioorg. Med. Chem. 2020, 28, 115557. |
| [15] | Afrasiabi, Z.; Sinn, E.; Lin, W. S.; Ma, Y. F.; Campana, C.; Padhye, S. J. Inorg. Biochem. 2005, 99, 1526. |
| [16] | Mishra, B. B.; Tiwari, V. K. Eur. J. Med. Chem., 2011, 46, 4769. |
| [17] | Mondal, S.; Bandyopadhyay, S.; Ghosh, M. K.; Mukhopadhyay, S.; Roy, S.; Mandal, C. Anti-Cancer Agents Med. Chem. 2012, 12, 49. |
| [18] | Newman, D. J.; Cragg, G. M.; Snader, K. M. J. Nat. Prod. 2003, 66, 1022. |
| [19] | Huang, J. L.; Xu, H. Curr. Top. Med. Chem. 2016, 16, 3365. |
| [20] | Pan, J. L.; Hao, X.; Yao, H. W.; Ge, K. K.; Ma, L.; Ma, W. J. For. Res. 2019, 30, 1105. |
| [21] | Sun, N.; Zhang, H.; Sun, P. P.; Khan, A.; Guo, J. H.; Zheng, X. Z.; Sun, Y. G.; Fan, K. H.; Yin, W.; Li, H. Q. Phytomedicine 2020, 77, 153289. |
| [22] | Zhang, B.; Liu, Z. Y.; Li, Y. Y.; Luo, Y.; Liu, M. L.; Dong, H. Y.; Wang, Y. X.; Liu, Y.; Zhao, P. T.; Jin, F. G.; Li, Z. C. Eur. J. Pharm. Sci. 2011, 44, 573. |
| [23] | Cheng, X. G.; He, H. Q.; Wang, W. X.; Dong, F. Y.; Zhang, H. H.; Ye, J. M.; Tan, C. C.; Wu, Y. H.; Lv, X. J.; Jiang, X. H.; Qin, X. J. Pest Manage. Sci. 2020, 76, 2711. |
| [24] | Zhou, S. K.; Zhang, R. L.; Xu, Y. F.; Bi, T. N. Molecules 2012, 17, 6481. |
| [25] | Chen, M. H.; Gu, Y. Y.; Zhang, A. L.; Sze Daniel, M. Y.; Mo, S. L.; May Brian, H. Pharmacol. Res. 2021,171. |
| [26] | Zhang, X.; Hou, G. Q.; Liu, A. D.; Xu, H.; Guan, Y.; Wu, Y. S.; Deng, J.; Cao, X. Cell Death Dis. 2019, 10, 10. |
| [27] | Liu, Z.-M.; Yang, X.-L.; Jiang, F.; Pan, Y.-C.; Zhang, L. J. Cell. Biochem. 2019, 121, 3. |
| [28] | Hu, J.; Wang, Y. Chin. Arch. Tradit. Chin. Med. 2021, 171. (in Chinese) |
| [28] | (胡锦丹, 王宇, 中华中医药学刊, 2021, 171.) |
| [29] | Dai, M.; Cai, Z.; Chen, N.; Li, J.; Wen, J.; Tan, L.; Guo, D. J. South. Med. Univ. 2019, 39, 1239. (in Chinese) |
| [29] | (戴美琴, 蔡茁, 陈娜娜, 李金州, 温嘉泳, 谭丽转, 郭丹, 南方医科大学学报, 2019, 39, 1239.) |
| [30] | Yang, J.; He, D.; Peng, Y.; Zhong, H.; Deng, Y.; Yu, Z.; Guan, C.; Zuo, Y.; Xu, Z. OncoTargets Ther. 2017, 10, 5209. |
| [31] | Fu, S.; Zhao, N.; Jing, G.; Yang, X.; Liu, J.; Zhen, D.; Tang, X. Biomed. Pharmacother. 2020, 128, 110327. |
| [32] | Li, Z.; Luo, M. Y.; Cai, B.; Wu, L. C.; Huang, M. T.; Rashid, H.; Jiang, J.; Wang, L. S. Bioorg. Med. Chem. Lett. 2018, 28, 677. |
| [33] | Wei, J.; Liang, Y.; Wu, L. Molecules 2021, 26, 417. |
| [34] | Sun, X.; Zhuo, X.-B.; Hu, Y.-P.; Zheng, X.; Zhao, Q.-J. Mol. Cell. Biochem. 2018, 449, 47. |
| [35] | Rashid, H.; Xu, Y.; Muhammad, Y.; Wang, L.; Jiang, J. Eur. J. Med. Chem. 2019, 161, 205. |
| [36] | Wang, M.; Huang, L.; Su, Y.; Xu, Y.-H.; Huang, L.-Y.; Zhou, X.-Q.; Li, F.-Y. Chemistry 2019, 82, 57. (in Chinese) |
| [36] | (王妙, 黄琳, 苏燕, 许英红, 黄铃月, 周小群, 李芳耀, 化学通报, 2019, 82, 57.) |
| [37] | Xin, M.; Pang, F.-H.; Huang, L.; Zhou, X.-Q.; Wang, M.-D.; Li, J.-L.; Li, F.-Y. Chin. J. Synth. Chem. 2020, 28, 483. (in Chinese) |
| [37] | (辛懋, 庞富华, 黄琳, 周小群, 王萌迪, 李金林, 李芳耀, 合成化学, 2020, 28, 483.) |
| [38] | Li, F.-Y.; Huang, L.; Li, Q.; Wang, X.; Ma, X. L.; Jiang, C. N.; Zhou, X. Q.; Duan, W. G.; Lei, F. H. Molecules 2019, 24, 4191. |
| [39] | Huang, L.; Huang, R.; Pang, F. H.; Li, A. K.; Huang, G. B.; Zhou, X. Q.; Li, Q.; Li, F. Y.; Ma, X. L. RSC Adv. 2020, 10, 18008. |
| [40] | Li, F. Y.; Huang, L.; Zhou, X. Q.; Li, Q.; Ma, X. L; Duan, W. G.; Wang, X. Chin. J. Org. Chem. 2020, 40, 2845. (in Chinese) |
| [40] | (李芳耀, 黄琳, 周小群, 李倩, 马献力, 段文贵, 王秀, 有机化学, 2020, 40, 2845.) |
| [41] | Zheng, W. L.; Ma, X. L.; Zhou, X. Q.; Li, F. Y.; Xin, M.; Jiang, C. N. Chem. Ind. For. Prod. 2019, 39, 41. (in Chinese) |
| [41] | (郑万里, 马献力, 周小群, 李芳耀, 辛懋, 蒋彩娜, 林产化学与工业, 2019, 39, 41.) |
| [42] | Wang, K.; Zheng, W. L; Jiang, C. N.; Zhou, X. Q.; Li, F. Y.; Xin, M.; Ma, X. L. Chem. Res. Appl. 2020, 32, 1377. (in Chinese) |
| [42] | (王珂, 郑万里, 蒋彩娜, 周小群, 李芳耀, 辛懋, 马献力, 化学研究与应用, 2020, 32, 1377.) |
| [43] | Huang, J. L.; Lv, M.; Xu, H. RSC Adv. 2017, 7, 15997. |
| [44] | Xu, H.; Su, X.; Liu, X. Q.; Zhang, K. P.; Hou, Z.; Guo, C. Bioorg. Med. Chem. Lett. 2019, 29, 126726. |
| [45] | Dai, B.; Ma, X.; Tang, Y.; Xu, L.; Guo, S.; Chen, X.; Lu, S.; Wang, G.; Liu, Y. Bioorg. Med. Chem. 2021, 29, 115891. |
| [46] | Ly, J. D.; Grubb, D. R.; Lawen, A. Apoptosis 2003, 8, 115. |
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