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

doi:10.7503/cjcu20160029

Abstract

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

CLC Number:

O614.81

TrendMD:

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

Figures/Tables 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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