细胞核定位的萘酰亚胺类衍生物的合成及抗肿瘤作用研究

doi:10.6023/cjoc202008015

有机化学 ›› 2021, Vol. 41 ›› Issue (4): 1599-1606.DOI: 10.6023/cjoc202008015 上一篇下一篇

研究论文

细胞核定位的萘酰亚胺类衍生物的合成及抗肿瘤作用研究

戎瑞雪^a^,^b, 李基民^a, 李耀文^a, 郭啸宇^a, 王冲^b, 李艳军^c, 李金梅^d, 韩宝君^c, 曹志然^a, 王克让^b^,^*(), 李小六^b^,^*()

a 河北大学基础医学院河北省炎性自身免疫性疾病发病机制及防治重点实验室河北保定 071000
b 河北大学化学与环境科学学院药物化学与分子诊断教育部重点实验室河北省化学生物学重点实验室河北保定 071002
c 保定市第一中心医院骨四科河北保定 071000
d 保定市第一中心医院病理科河北保定 071000

收稿日期:2020-08-11 修回日期:2020-09-15 发布日期:2020-12-31
通讯作者: 王克让, 李小六
基金资助:
国家自然科学基金(21572044); 国家自然科学基金(21778013); 河北省自然科学基金(B2017201193); 河北省卫生健康委员会基金(20202217); 大学生创新项目(201910075009); 大学生创新项目(2020338); 河北大学高层次人才科研启动基金(521000981311)

Synthesis and Anti-tumor Effects of Naphthalimide Derivatives Targeted in Cell Nucleus

Ruixue Rong^a^,^b, Jimin Li^a, Yaowen Li^a, Xiaoyu Guo^a, Chong Wang^b, Yanjun Li^c, Jinmei Li^d, Baojun Han^c, Zhiran Cao^a, Kerang Wang^b^,^*(), Xiaoliu Li^b^,^*()

a College of Basic Medicine, Key Laboratory of Pathogenesis Mechanism and Control of Inflammatory-autoimmune Diseases in Hebei Province, Hebei University, Baoding, Hebei 071000
b College of Chemistry and Environmental Science, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis (Ministry of Education), Key Laboratory of Chemical Biology of Hebei Province, Hebei University, Baoding, Hebei 071002
c Forth Department of Orthopedic, Baoding First Central Hospital, Baoding, Hebei 071000
d Department of Pathology, Baoding First Central Hospital, Baoding, Hebei 071000

Received:2020-08-11 Revised:2020-09-15 Published:2020-12-31
Contact: Kerang Wang, Xiaoliu Li
About author:
* Corresponding authors. E-mail: kerangwang@hbu.edu.cn;
E-mail: lixl@hbu.edu.cn
Supported by:
National Natural Science Foundation of China(21572044); National Natural Science Foundation of China(21778013); Natural Science Foundation of Hebei Province(B2017201193); Foundation of Health Commission of Hebei Province(20202217); Innovation Project of Students(201910075009); Innovation Project of Students(2020338); Hebei University High-level Talent Research Startup Project(521000981311)

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摘要/Abstract

以4-溴-1,8-萘酐为原料, 经亲核取代反应合成了系列手性氨基醇修饰的萘酰亚胺衍生物NI1~NI8. 四甲基偶氮唑蓝(MTT)法研究了其细胞毒性, 发现含有伯羟基氨基醇修饰的萘酰亚胺衍生物中R型的细胞毒性好于S型异构体. 经紫外光谱、荧光光谱和激光共聚焦实验研究了化合物(R)-2-(2-(二甲基氨基)乙基)-6-((1-羟基-2-丙烷基)氨基)-萘酰亚胺(NI1)和(S)-2-(2-(二甲基氨基)乙基)-6-((1-羟基-2-丙烷基)氨基)-萘酰亚胺(NI2)与DNA分子和HeLa细胞的相互作用, 发现其能有效与脱氧核糖核酸(DNA)络合, 键合常数达到10⁴ L?mol^–1; 且NI1和NI2与HeLa细胞作用可定位于细胞核. 流式细胞实验结果显示NI1和NI2能够使细胞周期阻滞于S期而抑制细胞增殖. 小鼠体内血液毒性结果显示NI1对血液中的红细胞、白细胞和血小板无明显影响.

关键词: 萘酰亚胺, 细胞核, 手性, 细胞周期

A series of novel chiral amino alcohol modified naphthalimide derivatives NI1~NI8 were designed and synthesized by nucleophilic substitution reaction. Furthermore, their cytotoxicities were studied by thiazolyl blue tetrazolium bromide (MTT) method. The cytotoxicity of the R-type isomer in the naphthalimide derivatives with primary hydroxyl amino alcohol modification was better than that of the S-type isomer. In addition, deoxyribonucleic acid (DNA) binding interactions and fluorescence imaging of (R)-2-(2-(dimethylamino)ethyl)-6-((1-hydroxypropan-2-yl)amino)-naphthalimide (NI1) and (S)-2-(2-(dimethylamino)ethyl)-6-((1-hydroxypropan-2-yl)amino)-naphthalimid (NI2) with Ct-DNA and HeLa cells were investigated. NI1 and NI2 showed strong binding interactions with Ct-DNA with a bonding constant of 10⁴ L/mol. And NI1 and NI2 exhibited nucleus-targeting imaging for HeLa cells. NI1 and NI2 mainly arrested the S phase. Moreover, the hematoxic results of NI1in mice showed no significant effects on the red blood cells, white blood cells and platelets in the blood.

Key words: naphthalimide, nucleus, chiral, cell cycle

引用此文

戎瑞雪, 李基民, 李耀文, 郭啸宇, 王冲, 李艳军, 李金梅, 韩宝君, 曹志然, 王克让, 李小六. 细胞核定位的萘酰亚胺类衍生物的合成及抗肿瘤作用研究[J]. 有机化学, 2021, 41(4): 1599-1606.

Ruixue Rong, Jimin Li, Yaowen Li, Xiaoyu Guo, Chong Wang, Yanjun Li, Jinmei Li, Baojun Han, Zhiran Cao, Kerang Wang, Xiaoliu Li. Synthesis and Anti-tumor Effects of Naphthalimide Derivatives Targeted in Cell Nucleus[J]. Chinese Journal of Organic Chemistry, 2021, 41(4): 1599-1606.

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图/表 6

图式1. NI1~NI8的合成路线

Scheme 1. Synthetic route of compounds NI1~NI8 Reagents and conditions: (1) EtOH, reflux; (2) (R)-2-amino-1-pro- panol, (S)-2-amino-1-propanol, (R)-1-amino-2-propanol, (S)-1- amino-2-propanol, (R)-2-aminobutanol, (S)-2-aminobutanol, (R)-3- amino-1,2-propanediol or (S)-3-amino-1,2-propanediol, HOCH2- CH2OCH3, DIPEA, reflux

Compd.	IC₅₀/(μmol?L^–1)
Compd.	HeLa	MCF-7	A549	MGC-803
NI1 (R)	4.76±0.05	14.44±0.04	1.51±0.01	16.79±0.53
NI2 (S)	8.03±0.03	32.59±0.01	3.47±0.06	28.38±0.49
NI3 (S)	3.99±0.05	11.64±0.01	4.33±0.04	17.33±0.41
NI4 (R)	7.79±0.02	17.69±0.04	22.15±0.05	29.14±0.33
NI5 (R)	6.42±0.02	11.56±0.02	5.86±0.04	7.82±0.37
NI6 (S)	13.58±0.04	25.40±0.01	30.99±0.03	19.04±0.34
NI7 (S)	11.89±0.04	70.43±0.02	17.66±0.01	63.44±0.33
NI8 (R)	5.84±0.04	71.05±0.02	8.745±0.04	34.71±0.35
Amonafide	3.40±0.03	6.79±0.02	1.99±0.08	3.23±0.43
Cisplatin	6.45±0.03	13.11±0.01	17.00±0.01	8.87±0.24

表1. 化合物NI1~NI8的细胞毒性

Table 1. Cytotoxic activity of compounds NI1~NI8

图1. 磷酸盐缓冲液中(10 mmol/L, pH 7.4, 50 mmol/L NaCl) NI1 (a, 1×10–5 mol/L)和NI2 (b, 1×10–5 mol/L)与Ct-DNA的作用的紫外光谱

Figure 1. UV-Vis spectra of NI1 (a, 1×10–5 mol/L) and NI2 (b, 1×10–5 mol/L) binding with Ct-DNA in PBS buffer (10 mmol/L, pH 7.4, 50 mmol/L NaCl) Inset: the fitting curve of NI1and NI2binding with Ct-DNA

图2. NI1 (2 μmol/L, λ ex=405 nm)和NI2 (2 μmol/L, λ ex=405 nm)与HeLa细胞作用的荧光成像(λex=405 nm)

Figure 2. Fluorescence images of NI1 (2 μmol/L, λ ex=405 nm) and NI2 (2 μmol/L, λ ex=405 nm) incubation with HeLa cells

图3. HeLa细胞(A)与化合物NI1 (B)和NI2 (C)作用的细胞周期

Figure 3. Cell cycle analysis of HeLa cells (A) incubation with NI1 (B) and NI2 (C)

分组	浓度/(mg?mL^–1)	WBC/(10⁹ L^–1)	RBC/(10¹² L^–1)	PLT/(10⁹ L^–1)
Control	0	4.85±0.11	9.35±0.66	358.64±257.71
24 h	5	5.94±0.52^a	8.67±0.29^a	550.33±74.09^a
	10	5.68±0.26^a	9.23±0.33^a	465.33±34.12^a
	20	5.83±0.25^a	9.43±0.38^a	475.00±119.80^a
48 h	5	4.52±1.19^a	9.12±0.40^a	562.33±9.29^a
	10	5.23±1.24^a	9.44±1.46^a	563.33±83.34^a
	20	4.57±0.50^a	7.77±0.87^a	720.00±336.79^a
96 h	5	5.71±0.43^a	9.16±0.23^a	233.33±65.61^a
	10	5.63±0.30^a	9.48±0.12^a	320.00±161.61^a
	20	5.34±0.51^a	6.52±0.22^a	927.00±213.55^a

表2. 化合物NI1对小鼠的血液毒性( $\bar{x}$±s)

Table 2. Hematological toxicity of compound NI1 in mice ( $\bar{x}$±s)

参考文献 27

[1]	Tiwari, R.; Jain, P.; Asati, S.; Haider, T.; Soni, V.; Pandey, V. J. Drug Delivery Sci. Technol. 2018, 48,383. doi: 10.1016/j.jddst.2018.10.011
[2]	Wang, G.H.; Chen, H.; Cai, Y.Y.; Li, L.; Yang, H.K.; Li, Q.; He, Z.J.; Lin, J.T. Mater. Sci. Eng. C 2018, 90,568. doi: 10.1016/j.msec.2018.05.013
[3]	(a) Ahmad, M.Z.; Akhter, S.; Rahman, Z.; Akhter, S.; Anwar, M.; Mallik, N.; Ahmad, F.J. J. Pharm. Pharmacol. 2013, 65,634. doi: 10.1111/jphp.12017 pmid: 28333438
	(b) Ali, M.R. K.; Wu, Y.; Ghosh, D.; Do, B.H.; Chen, K.; Dawson, M.R.; Fang, N.; Sulchek, T.A.; El-Sayed, M.A. ACS Nano 2017, 11,3716. doi: 10.1021/acsnano.6b08345 pmid: 28333438
[4]	(a) Pan, L.M.; Shi, J.L. Chin. J. Chem. 2018, 36,481. doi: 10.1002/cjoc.v36.6
	(b) Marshall, W.F. Curr. Biol. 2002, 12,185.
[5]	Dey, P. Diagn. Cytopathol. 2010, 38,382. doi: 10.1002/dc.21234 pmid: 19894267
[6]	Zink, D.; Fischer, A.H.; Nickerson, J.A. Nat. Rev. Cancer 2004, 4,677. doi: 10.1038/nrc1430 pmid: 15343274
[7]	Peng, H.B.; Tang, J.; Zheng, R.; Guo, G.N.; Dong, A.G.; Wang, Y.J.; Yang, W.L. Adv. Healthcare Mater. 2017, 6,1601289. doi: 10.1002/adhm.v6.7
[8]	(a) Michalak, E.M.; Burr, M.L.; Bannister, A.J.; Dawson, M.A. Nat. Rev. Mol. Cell Biol. 2019, 20,573. doi: 10.1038/s41580-019-0143-1 pmid: 28375569
	(b) Tandon, R.; Luxami, V.; Kaur, H.; Tandon, K.; Paul, K. Chem. Rec. 2017, 17,956. pmid: 28375569
[9]	Zhou, J.; Chang, A.; Wang, L.L.; Liu, Y.; Liu, X.J.; Shangguan, D.H. Org. Biomol. Chem. 2014, 56,9207.
[10]	Zhang, H.; Wang, K.; Xuan, X.P.; Lv, Q.Z.; Nie, Y.M.; Guo, H.M. Chem. Commun. 2016, 52,6308. doi: 10.1039/C6CC02290A
[11]	Singh, K.; Rotaru, A.M.; Beharry, A.A. ACS Chem. Biol. 2018, 13,1785. doi: 10.1021/acschembio.8b00014 pmid: 29579380
[12]	Skok, Ž.; Zidar, N.; Kikelj, D.; Ilaš, J. J. Med. Chem. 2020, 63,884. doi: 10.1021/acs.jmedchem.9b00726 pmid: 31592646
[13]	Liu, J.; Liu, X.J.; Lu, S.S.; Zhang, L.L.; Feng, L.; Zhong, S.L.; Zhang, N.; Bing, T.; Shangguan, D.H. Analyst 2020, 145,6549. pmid: 32776047
[14]	Fueyo-González, F.; Fernández-Gutiérrez, M.; García-Puentes, D.; Orte, A.; González-Vera, J.A.; Herranz, R. Eur. J. Med. Chem., 2020, 200,112407. doi: 10.1016/j.ejmech.2020.112407 pmid: 32512480
[15]	Wu, Z.; Liu, M.; Liu, Z.; Tian, Y. J. Am. Chem. Soc. 2020, 142,7532. doi: 10.1021/jacs.0c00771 pmid: 32233469
[16]	Feng, H.; Meng, Q.T.; Ta, H.T.; Zhang, R. New J. Chem. 2020, 44,12890. doi: 10.1039/D0NJ02762F
[17]	Wang, K.R.; Qian, F.; Sun, Q.; Ma, C.L.; Rong, R.X.; Cao, Z.R.; Wang, X.M.; Li, X.L. Chem. Biol. Drug Des. 2016, 87,664. doi: 10.1111/cbdd.12698 pmid: 26648338
[18]	Rong, R.X.; Wang, S.S.; Liu, X.; Li, R.F.; Wang, K.R.; Cao, Z.R.; Li, X.L. Bioorg. Med. Chem. Lett. 2018, 28,742. doi: 10.1016/j.bmcl.2018.01.008 pmid: 29342415
[19]	Wang, K.R.; Qian, F.; Rong, R.X.; Cao, Z.R.; Wang, X.M.; Li, X.L. RSC Adv. 2014, 4,47605.
[20]	Rong, R.X.; Sun, Q.; Ma, C.L.; Chen, B.; Wang, W.Y.; Wang, Z.A.; Wang, K.R.; Li, X.L. Med. Chem. Commun. 2016, 7,679.
[21]	Wang, K.R.; An, H.W.; Wang, Y.Q.; Yan, X.H.; Li, Y.; Chen, H.; Zhang, P.Z.; Li, J.M.; Li, X.L.; Zhang, J.C. Chin. J. Org. Chem. 2012, 32,696. (in Chinese)
	( 王克让, 安红维, 王月清, 闫新豪, 李锐, 陈华, 张平竹, 李金梅, 李小六, 张金超, 有机化学, 2012, 32,696.)
[22]	Sharma, H.; Sidhu, J.S.; Hassen, W.M.; Singh, N.; Dubowski, J.J. ACS Omega 2019, 4,5829.
[23]	Elmes, R.B. P.; Ryan, G.J.; Erby, M.L.; Frimannsson, D.O.; Kitchen, J.A.; Lawler, M.; Williams, D.C.; Quinn, S.J.; Gunnlaugsson, T. Inorg. Chem. 2020, 59,10874.
[24]	Petrova, N.V.; Velichko, A.K.; Razin, S.V.; Kantidze, O.L. Cell Cycle 2016, 15,337.
[25]	(a) Bai, T.; Zhu, B.; Shao, D.; Lian, Z.; Liu, P.; Shi, J.; Kong, J. Macromol. Biosci. 2020, 20,e1900438.
	(b) Wang, S.S.; Zhang, Q.L.; Chu, P.; Kong, L.Q.; Li, G.Z.; Li, Y.Q.; Yang, L.; Zhao, W.J.; Guo, X.H.; Tang, Z.Y. Bioorg. Chem. 2020, 101,104036.
[26]	Wang, K.R.; Qian, F.; Wang, X.M.; Tan, G.H.; Rong, R.X.; Cao, Z.R.; Chen, H.; Zhang, P.Z.; Li, X.L. Chin. Chem. Lett. 2014, 25,1087.
[27]	Banerjee, S.; Veale, E.B.; Phelan, C.M.; Murphy, S.A.; Tocci, G.M.; Gillespie, L.J.; Frimannsson, D.O.; Kelly, J.M.; Gunnlaugsson, T. Chem. Soc. Rev. 2013, 42,1601.

细胞核定位的萘酰亚胺类衍生物的合成及抗肿瘤作用研究

Synthesis and Anti-tumor Effects of Naphthalimide Derivatives Targeted in Cell Nucleus

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