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

doi:10.6023/cjoc202008015

Chinese Journal of Organic Chemistry ›› 2021, Vol. 41 ›› Issue (4): 1599-1606.DOI: 10.6023/cjoc202008015 Previous Articles Next Articles

ARTICLES

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)

1. cjoc202008015.pdf(2343KB)

Abstract

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

Cite this article

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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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

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

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

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

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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