含磺酰胺基团苯并噻二唑荧光染料的合成及其肿瘤细胞长效示踪应用研究

doi:10.6023/cjoc202202037

摘要/Abstract

开发具有抗光漂白、斯托克斯位移(Stokes shift)大、生物相容性优异等特性的肿瘤细胞长效示踪应用型荧光染料已成为现阶段生物成像领域的研究热点. 本工作以具有优异光学性质的苯并噻二唑(BTD)为荧光母核, 通过引入N,N-二甲基取代磺酰胺基团提升荧光染料的生物相容性及溶解性, 设计合成了给体-受体-给体(D-A-D)型荧光染料(SIBIS). SIBIS具有聚集诱导发光效应(AIE)、较大的Stokes shift (155 nm)、极低的细胞毒性等特性. 不同细胞系内吞结果表明SIBIS可靶向活细胞溶酶体, 肿瘤细胞内长效示踪研究表明SIBIS可有效示踪小鼠乳腺癌4T1细胞分裂15代以上. 因此, SIBIS可作为肿瘤细胞长效示踪剂, 并有望应用于溶酶体相关炎症和疾病示踪.

关键词: 肿瘤细胞长效示踪, 苯并噻二唑, N,N-二甲基取代磺酰胺, 聚集诱导发光

To develop long-term cancer cell tracking dyes with anti-photobleaching, large Stokes shift, and excellent biocompatibility is the research hotspot in the field of biological imaging. In this study, a donor-acceptor-donor (D-A-D) stuctured benzothiadiazole (BTD)-based fluorescent dye was sythesized, namely SIBIS. The BTD with excellent optical properties was chosen as the core stucture and the N,N-dimethyl substituted sulfonamide was selceted to improve the biocompatibility and solubility of fluorescent dye. SIBIS possessed aggregation-induced emission (AIE), large Stokes shift (155 nm) and low cytotoxicity. The endocytosis results in different cell lines showed that SIBIS could target lysosome of living cells. The long-term 4T1 cell tracking results showed that SIBIS could effectively trace cell divisions for more than 15 generations. Therefore, SIBIS can serve as a kind of promising long-term cell traking agents tumor cells, and has a great potential for further biological applications for tracking various kinds of lysosomal related inflammation and diseases.

Key words: long-term cancer cell tracking, benzothiadiazole, N,N-dimethyl substituted sulfonamide, aggregation-induced emission

引用此文

夏伟康, 刘闯, 叶盛, 汪磊, 刘瑞源. 含磺酰胺基团苯并噻二唑荧光染料的合成及其肿瘤细胞长效示踪应用研究[J]. 有机化学, 2022, 42(8): 2535-2541.

Weikang Xia, Chuang Liu, Sheng Ye, Lei Wang, Ruiyuan Liu. Synthesis of A Sulfonamide-Substituted Benzothiadiazole-Based Fluorescent Dye and Study of Its Application for Long-Term Cancer Cell Tracking[J]. Chinese Journal of Organic Chemistry, 2022, 42(8): 2535-2541.

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

分享此文

图/表 6

Scheme 1. Synthetic route of SIBIS

Figure 1. (a) UV-vis absorption spectra of SIBIS in different solvents; (b) FL spectra of SIBIS in different solvents; (c) UV-vis absorption spectra of SIBIS in the DMSO/water mixtures with different water fractions (fw); (d) FL spectra of SIBIS in the DMSO/water mixtures with different water fractions (fw)

Figure 2. Cell viabilities of cell lines including 4T1 cells, HeLa cells, and MCF-7 cells co-stained with different SIBIS concentrations

Figure 3. CLSM images of cells lines including 4T1 cells, HeLa cells, MCF-7 cells after incubation with SIBIS (0.5 μmol/L, 6 h) and Lyso-Tracker Red (100 nmol/L, 0.5 h) in sequence (sale bar: 10 μm)

Figure 4. CLSM images of 4T1 cells co-stained with SIBIS (0.5 μmol/L) at different generations (scale bar: 10 μm)

Figure 5. Flow cytometry profiles of SIBIS co-stained 4T1 cells at different generations

参考文献 43

[1]	Siegel, R. L.; Miller, K. D.; Fuchs, H. E.; Jemal, A. Ca-Cancer J. Clin. 2021, 71, 7. doi: 10.3322/caac.21654
[2]	Shi, J.; Kantoff, P. W.; Wooster, R.; Farokhzad, O. C. Nat. Rev. Cancer 2017, 17, 20. doi: 10.1038/nrc.2016.108
[3]	Dhanasekaran, R.; Deutzmann, A.; Mahauad-Fernandez, W. D.; Hansen, A. S.; Gouw, A. M.; Felsher, D. W. Nat. Rev. Clin. Oncol. 2022, 19, 23. doi: 10.1038/s41571-021-00549-2
[4]	Blanpain, C. Nat. Cell Biol. 2013, 15, 126. doi: 10.1038/ncb2657 pmid: 23334500
[5]	Chen, Z.; Li, J.; Chen, X.; Cao, J.; Zhang, J.; Min, Q.; Zhu, J. J. J. Am. Chem. Soc. 2015, 137, 1903. doi: 10.1021/ja5112628
[6]	Ning, X.; Bao, H.; Liu, X.; Fu, H.; Wang, W.; Huang, J.; Zhang, Z. Nanoscale 2019, 11, 20932. doi: 10.1039/C9NR05637H
[7]	Das, B.; Girigoswami, A.; Pal, P.; Dhara, S. Mater. Sci. Eng.,C 2019, 102, 427. doi: 10.1016/j.msec.2019.04.077
[8]	Song, L.; Lin, X. H.; Song, X. R.; Chen, S.; Chen, X. F.; Li, J.; Yang, H. H. Nanoscale 2017, 9, 2718. doi: 10.1039/C6NR09553D
[9]	Ma, H.; Hu, D.; Zhao, J.; Tian, M.; Yuan, J.; Wei, Y. CCS Chem. 2021, 3, 1569. doi: 10.31635/ccschem.020.202000383
[10]	Wang, Z. L.; Qiao, R. R.; Tang, N.; Lu, Z. W.; Wang, H.; Zhang, Z. X.; Xue, X. D.; Huang, Z. Y.; Zhang, S. R.; Zhang, G. X.; Li, Y. P. Biomaterials 2017, 127, 25. doi: 10.1016/j.biomaterials.2017.02.037
[11]	Kikuchi, K. Chem. Soc. Rev. 2010, 39, 2048. doi: 10.1039/b819316a pmid: 20372693
[12]	Geng, X.; Sun, Y.; Li, Z.; Yang, R.; Zhao, Y.; Guo, Y.; Xu, J.; Li, F.; Wang, Y.; Lu. S.; Qu, L. Small 2019, 15, 1901517. doi: 10.1002/smll.201901517
[13]	Chen, X.; Zhang, X.; Xia, L. Y.; Wang, H. Y.; Chen, Z.; Wu, F. G. Nano Lett. 2018, 18, 1159. doi: 10.1021/acs.nanolett.7b04700
[14]	Yang, Z.; Wang, X.; Liang, G.; Yang, A.; Li, J. J. Mater. Chem. B 2022, 10, 518. doi: 10.1039/D1TB02074A
[15]	Andreiuk, B.; Reisch, A.; Lindecker, M.; Follain, G.; Peyriéras, N.; Goetz, J. G.; Klymchenko, A. S. Small 2017, 13, 1701582. doi: 10.1002/smll.201701582
[16]	Xia, Q.; Chen, Z. K.; Zhang, Z. D.; Liu, R. Y. Chin. J. Org. Chem. 2018, 38, 2700. (in Chinese) doi: 10.6023/cjoc201803029
	(夏琦, 陈子康, 张志德, 刘瑞源, 有机化学, 2018, 38, 2700.) doi: 10.6023/cjoc201803029
[17]	Li, D.; Qin, W.; Xu, B.; Qian, J.; Tang, B. Z. Adv. Mater. 2017, 29, 1703643. doi: 10.1002/adma.201703643
[18]	Yong, K.-T.; Law, W.-C.; Hu, R.; Ye, L.; Liu, L.; Swihart, M. T.; Prasad, P. N. Chem. Soc. Rev. 2013, 42, 1236. doi: 10.1039/C2CS35392J
[19]	Kaur, P.; Singh, K. J. Mater. Chem. C 2019, 7, 11361. doi: 10.1039/C9TC03719E
[20]	Xie, J.; Wang, L.; Su, X.; Rodrigues, J. Curr. Org. Chem. 2021, 25, 2142. doi: 10.2174/1385272825666210728101823
[21]	Yu, H. X.; Zhi, J.; Chang, Z. F.; Shen, T.; Ding, W. L.; Zhang, X.; Wang, J. L. Mater. Chem. Front. 2019, 3, 151. doi: 10.1039/C8QM00424B
[22]	Li, Y.; Zhou, Y.; Yue, X.; Dai, Z. Adv. Healthcare Mater. 2020, 9, 2001327. doi: 10.1002/adhm.202001327
[23]	Yu, C. J.; Guo, X.; Fang, X. B.; Chen, N.; Wu, Q. H.; Hao, E. H.; Jiao, L. J. Dyes Pigm. 2022, 197, 109838. doi: 10.1016/j.dyepig.2021.109838
[24]	Yu, C. J.; Fang, X. B.; Wang, H.; Guo, X.; Sun, L. L.; Wu, Q. H.; Jiao, L. J.; Hao, E. H. J. Org. Chem. 2021, 86, 11492. doi: 10.1021/acs.joc.1c01042
[25]	Guo, X.; Tang, B.; Wu, H.; Wu, Q. H.; Xie, Z.Y.; Yu, C. J.; Hao, E. H.; Jiao, L. J. Mater. Chem. Front. 2021, 5, 3664. doi: 10.1039/D1QM00067E
[26]	Shi, Z. X.; Han, X.; Hu, W. B.; Bai, H.; Peng, B.; Ji, L.; Fan, Q. L.; Li, L.; Huang, W. Chem. Soc. Rev. 2020, 49, 7533. doi: 10.1039/D0CS00234H
[27]	Fan, G. W.; Wang, N. N.; Zhang, J.; Ji, X.; Qi, S. C.; Tao, Y. F.; Zhao, W. L. Dyes Pigm. 2022, 199, 110073. doi: 10.1016/j.dyepig.2021.110073
[28]	Pham, T. C.; Nguyen, V. N.; Choi, Y.; Lee, S.; Yoon, J. Chem. Rev. 2021, 121, 13454. doi: 10.1021/acs.chemrev.1c00381
[29]	Chi, C. Y.; Mikhailovsky, A.; Bazan, G. C. J. Am. Chem. Soc. 2007, 129, 11134. doi: 10.1021/ja072471s
[30]	Neto, B. A.; Carvalho, P. H.; Correa, J. R. Acc. Chem. Res. 2015, 48, 1560. doi: 10.1021/ar500468p
[31]	Yao, H.; Dai, J.; Zhuang, Z.; Yao, J.; Wu, Z.; Wang, S.; Xia, F.; Zhou, J.; Lou, X. D.; Zhao, Z. Z. Sci. China: Chem. 2020, 63, 1815.
[32]	Wang, L.; Xia, Q.; Hou, M. R.; Yan, C. G.; Xu, Y.; Qu, J. Q.; Liu, R. R. J. Mater. Chem. B 2017, 5, 9183. doi: 10.1039/c7tb02668d pmid: 32264600
[33]	Liu, J.; Li, K.; Liu, B. Adv. Sci. 2015, 2, 1500008. doi: 10.1002/advs.201500008
[34]	Qin, W.; Li, K.; Feng, G.; Li, M.; Yang, Z.; Liu, B.; Tang, B. Z. Adv. Funct. Mater. 2014, 24, 635. doi: 10.1002/adfm.201302114
[35]	Bujacz, G.; Alexandratos, J.; Wlodawer, A.; Merkel, G.; Andrake, M.; Katz, R. A.; Skalka, A. M. J. Biol. Chem. 1997, 272, 18161. doi: 10.1074/jbc.272.29.18161 pmid: 9218451
[36]	Tamura, T.; Ueda, T.; Goto, T.; Tsukidate, T.; Shapira, Y.; Nishikawa, Y.; Fujisawa, A.; Hamachi, I. Nat. Commun. 2018, 9, 1870. doi: 10.1038/s41467-018-04343-0
[37]	Wang, L.; Tran, M.; D’Este, E.; Roberti, J.; Koch, B.; Xue, L.; Johnsson, K. Nat. Chem. 2020, 12, 165. doi: 10.1038/s41557-019-0371-1 pmid: 31792385
[38]	Gao, S.; Yu, S.; Zhang, Y.; Wu, A.; Zhang, S.; Wei, G.; Wang, H.; Xiao, Z.; Lu, W. Adv. Funct. Mater. 2021, 31, 2008356. doi: 10.1002/adfm.202008356
[39]	Yang, Z.; Zhang, Z.; Sun, Y.; Lei, Z.; Wang, D.; Ma, H.; Tang, B. Z. Biomaterials 2021, 275, 120934. doi: 10.1016/j.biomaterials.2021.120934
[40]	Tian, X. Q.; Zuo, M. Z.; Niu, P. B.; Wang, K. Y.; Hu, X. Y. Chin. J. Org. Chem. 2020, 40, 1823. (in Chinese) doi: 10.6023/cjoc202003066
	(田雪琪, 左旻瓒, 牛蓬勃, 王开亚, 胡晓玉, 有机化学, 2020, 40, 1823.) doi: 10.6023/cjoc202003066
[41]	Wang, L. F.; Qian, Y. Chin. J. Org. Chem. 2020, 40, 1246. (in Chinese) doi: 10.6023/cjoc201911022
	(王凌锋, 钱鹰, 有机化学, 2020, 40, 1246.) doi: 10.6023/cjoc201911022
[42]	Bock, L.; Miller, G. H.; Schaper, K. -J.; Seydel, J. K. J. Med. Chem. 1974, 17, 23. pmid: 4357096
[43]	Rousseau, J. F.; Dodd, R. H. Heterocycles 2001, 55, 2289. doi: 10.3987/COM-01-9320