咔咯钴(Ⅲ)配合物与DNA的相互作用及抗肿瘤活性

doi:10.7503/cjcu20160029

高等学校化学学报 ›› 2016, Vol. 37 ›› Issue (6): 1059.doi: 10.7503/cjcu20160029

• 研究论文: 无机化学 • 上一篇下一篇

咔咯钴(Ⅲ)配合物与DNA的相互作用及抗肿瘤活性

史蕾¹(), 杨文聪¹, 曾淑莹¹, 莫婷婷¹, 张召², 曹曼丽¹, 刘海洋²()

1. 广东第二师范学院化学系, 广州 510303
2. 华南理工大学化学系, 广州 510641

收稿日期:2016-01-13 出版日期:2016-06-10 发布日期:2016-05-26
作者简介:联系人简介: 史蕾, 女, 博士, 讲师, 主要从事咔咯大环化合物的合成及生物学性质研究. E-mail:shil@gdei.edu.cn;刘海洋, 男, 博士, 教授, 主要从事咔咯大环化合物的合成及性质研究. E-mail:chhyliu@scut.edu.cn
基金资助:
国家自然科学基金(批准号: 21171057, 21371059)、广东省自然科学基金(批准号: S2012040006270)、广东大学生科技创新培育专项资金(攀登计划专项资金)和国家级大学生创新创业训练计划项目(批准号: 201514278005)资助

DNA-binding and Anti-tumor Activities of Cobalt Corrole Complexes^†

SHI Lei^1,^*(), YANG Wencong¹, ZENG Shuying¹, MO Tingting¹, ZHANG Zhao², CAO Manli¹, LIU Haiyang^2,^*()

1. Department of Chemistry, Guangdong University of Education, Guangzhou 510303, China
2. Department of Chemistry, South China University of Technology, Guangzhou 510641, China

Received:2016-01-13 Online:2016-06-10 Published:2016-05-26
Contact: SHI Lei,LIU Haiyang E-mail:shil@gdei.edu.cn;chhyliu@scut.edu.cn
Supported by:
† Supported by the National Natural Science Foundation of China(Nos.21171057, 21371059), the Natural Science Foundation of Guangdong Province, China(No.S2012040006270), the Science and Technology Innovation Foundation of Guangdong University Students(Special Foundation for Glimbing Plan) of China and the National Training Programs of Innovation and Entrepreneurship for Undergraduates(No.201514278005)

摘要/Abstract

摘要：

合成了10-(4-羟基苯基)-5,15-二(五氟苯基)咔咯钴(Ⅲ)配合物(1-Co)和10-(4-吩噻嗪苯基)-5,15-二(五氟苯基)咔咯钴(Ⅲ)配合物(2-Co), 并采用核磁共振波谱、质谱和紫外-可见光谱等对其结构进行了表征, 利用紫外光谱、荧光光谱、圆二色谱、黏度测试和琼脂糖凝胶电泳等技术研究了配合物1-Co和2-Co与小牛胸腺DNA(ct-DNA)之间的相互作用. 结果表明, 配合物1-Co和2-Co与DNA之间的作用模式为外部结合, 且在光照下均能引发DNA断裂. 细胞毒性实验结果表明, 配合物1-Co和2-Co具有很低的暗细胞毒性, 但在光照条件下均能有效抑制H460, HeLa, A549等肿瘤细胞株增殖, 表明配合物1-Co和2-Co在光动力治疗中具有潜在的应用价值. 细胞核染色和线粒体膜电位检测结果表明, 在光照条件下配合物2-Co可能是通过氧化损伤线粒体的途径抑制肿瘤细胞增殖.

关键词: 咔咯, 吩噻嗪, 卟啉, DNA, 抗肿瘤活性

Abstract:

10-(4-Hydroxylphenyl)-5,15-bis(pentafluorophenyl)corrolatocobalt(1-Co) and 10-(4-phenothiazine)-5,15-bis(pentafluorophenyl)corrolatocobalt(2-Co) were synthesized and characterized by NMR, HR-MS and UV-Vis spectrometries. The interactions of the two complexes with ct-DNA were studied by fluorescence, UV-Vis and circular dichroism spectrometries, viscosity measurements as well as agarose gel electrophoresis. The results suggested that complexes 1-Co and 2-Co both interact with DNA via an outside binding mode. Furthermore, the two cobalt corrole complexes can effectively cleavage DNA under irradiation. MTT experiments indicated that both complexes display low levels of dark toxicity, but have high photocytoto-xic activity against H460, HeLa and A549 cell lines. This implies complexes 1-Co and 2-Co may have potential application in photodynamic therapy(PDT) as photosensitizer. Through the observation of the nucleus morphological and the measurement of mitochondrial membrane potential, we speculated that complex 2-Co can constrain tumor cell proliferation through the oxidative damage of mitochondria possibly.

Key words: Corrole, Phenothiazine, Porphyrin, DNA, Anti-tumor activity

中图分类号:

O614.81

TrendMD:

史蕾, 杨文聪, 曾淑莹, 莫婷婷, 张召, 曹曼丽, 刘海洋. 咔咯钴(Ⅲ)配合物与DNA的相互作用及抗肿瘤活性. 高等学校化学学报, 2016, 37(6): 1059.

SHI Lei, YANG Wencong, ZENG Shuying, MO Tingting, ZHANG Zhao, CAO Manli, LIU Haiyang. DNA-binding and Anti-tumor Activities of Cobalt Corrole Complexes^†. Chem. J. Chinese Universities, 2016, 37(6): 1059.

图/表 12

Scheme 1 Molecular structures of mono-hydroxyl corrole(1), phenothiazine-corrole dyad(2) and their cobalt(Ⅲ) complexes(1-Co, 2-Co)

Fig.1 Changes in the UV-Vis spectra of complexes 1-Co(A), 2-Co(C)(1×10-5 mol/L) upon addition of ct-DNA and relationships between [DNA]/∣εa-εf∣and [DNA] during the interaction between 1-Co(B), 2-Co(D) and ct-DNA(A) [DNA]/(μmol·L-1) from a to j: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20; (C) [DNA]/(μmol·L-1) from a to i: 1, 2, 3, 4, 5, 6, 7, 8, 9.

Fig.2 Changes in the fluorescence spectra of ct-DNA-EB system upon addition of complex 1-Co at 298 K(A), 304 K(B), 310 K(C) and the plot of F0/F versus [1-Co] at different temperatures(D)[1-Co]/(μmol/L) from a to g: 0, 1, 2, 3, 4, 5, 6.

Table 1 Binding parameters of complexes 1-Co and 2-Co with DNA at different temperatures

Complex	Temperature/K	K_SV/(L·mol^-1)	K_q/(L·mol^-1·s^-1)	R
1-Co	298	5.22×10⁴	5.22×10¹²	0.994
	304	3.12×10⁴	3.12×10¹²	0.973
	310	2.41×10⁴	2.41×10¹²	0.970
2-Co	298	4.87×10⁴	4.87×10¹²	0.978
	304	4.83×10⁴	4.83×10¹²	0.994
	310	4.03×10⁴	4.03×10¹²	0.977

Fig.3 Changes in the fluorescence spectra of ct-DNA-EB system upon addition of complex 2-Co at 298 K(A), 304 K(B), 310 K(C) and the plot of F0/F versus [2-Co] at different temperatures(D)[2-Co]/(μmol·L-1) from a to f: 0, 1, 2, 3, 4, 5.

Fig.4 Effect of increasing amount of complexes 1-Co(A) and 2-Co(B) to the CD spectra of ct-DNA(150 μmol/L) in Tris-HCl buffer(T=298 K)

Fig.5 Effect of increasing amounts of EB(a), complexes 2-Co(b) and 1-Co(c) on the relative viscosities of ct-DNA(100 μmol/L)T=298 K.

Fig.6 UV-Vis spectra of 1-Co(A) and 2-Co(B) in DCM(10-5 mol/L)

Fig.7 Agarose gel electrophoresis patterns of 1-Co(A) or 2-Co(B) for the cleavage of supercoiled pBR 322 DNA(T=298 K)Reaction mixtures(10 μL) contained 0.1 μg of plasmid DNA, 1-Co or 2-Co. (A) Lane 1: DNA alone; lane 2: DNA(hν 2 h); lane 3: DNA+320 μmol/L 1-Co(no hν); lanes 4—8: DNA+40, 100, 160, 240, 320 μmol/L 1-Co respectively(hν 2 h). (B) Lane 1: DNA alone; lane 2: DNA(hν 2 h); lane 3: DNA+320 μmol/L 2-Co(no hν); lanes 4―8: DNA+40, 100, 160, 240, 320 μmol/L 2-Co respectively(hν 2 h).

Table 2 Inhibitory activity[IC50/(μmol·L-1)] of complex 1-Co or 2-Co against selected cell lines

Complex	H460		Hela		A549
Complex	Dark	Light	Dark	Light	Dark	Light
1-Co	84±5.1	29±3.2	104±5.7	36±2.9	113±5.1	31±2.8
2-Co	52±2.7	20±3.9	76±3.6	24±2.6	47±1.9	29±2.7

Fig.8 Fluorescence microscopic images of Hoechst-33342-stained H460 cells after treatment with complex 2-Co(20 μmol/L) for 24 h(×200)(A) Control+bright field; (B) control+hoechst; (C) control+merge; (D) 2-Co+bright field;(E) 2-Co+hoechst; (F) 2-Co+merge.

Fig.9 Effect of 2-Co and light on MMP decrease in H460 cells(×200) (A) JC-1+control; (B) JC-1+10 μmol/L 2-Co; (C) JC-1+20 μmol/L 2-Co.

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咔咯钴(Ⅲ)配合物与DNA的相互作用及抗肿瘤活性

DNA-binding and Anti-tumor Activities of Cobalt Corrole Complexes^†

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咔咯钴(Ⅲ)配合物与DNA的相互作用及抗肿瘤活性

DNA-binding and Anti-tumor Activities of Cobalt Corrole Complexes†

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DNA-binding and Anti-tumor Activities of Cobalt Corrole Complexes^†