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Acta Phys. -Chim. Sin.  2019, Vol. 35 Issue (2): 230-240    DOI: 10.3866/PKU.WHXB201711281
ARTICLE     
DNA Interactions and Cytotoxicity of Imidazole-Modified Naphthalimides
Yunyan GAO,Wenjiao CAI,Zhize OU*(),Tuotuo MA,Na YI,Zhiyuan LI
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Abstract  

The rational design of naphthalimide derivatives, which can target specific DNA sequences and secondary structural DNA, is important for developing potential anticancer drugs. In this work, the naphthalimide-imidazole conjugate (3) and its alkylated derivatives (4ac) were synthesized, and characterized by 1H NMR, 13C NMR, and mass spectrometry (MS). The interactions of these compounds with calf thymus DNA (CT DNA) and G-quadruplex DNA were investigated by UV-Vis spectroscopy, fluorescence spectroscopy, circular dichroism, and fluorescence resonance energy transfer (FRET). The studies revealed that the naphthalimides with imidazolium displayed higher affinity towards CT DNA than those with the imidazole moiety, suggesting that the electrostatic interaction plays an important role in the interactions between the naphthalimide and the DNA duplex. All of the obtained naphthalimide derivatives possessed high affinity (Ka > 4 × 106 L·mol-1) towards the telomeric G-quadruplex, and exhibited more than 30-fold selectivity for the quadruplex versus CT DNA. The viscosity of CT DNA increased upon addition of the naphthalimides, suggesting that the latter could bind to the former via a classical intercalation mode. FRET results indicated that the compounds 3 and 4ac stabilized the structure of the telomeric G-quadruplex by increasing its melting temperature by 5.8, 10.7, 8.4, and 7.8 ℃, respectively. CD spectral results suggested that the telomeric G-quadruplex maintained a mixture of antiparallel and parallel conformation in the presence of the naphthalimide derivatives (3 and 4ac) in a buffer containing K+. The fluorescence intensity of the naphthalimide derivatives 3 and 4a, b with octylimidazolium was significantly enhanced upon interaction with the G-quadruplex, which could be attributed to the immersion of naphthalimide moieties in the hydrophobic region of the G-quadruplex. However, the fluorescence of compound 4c with hexadecylimidazolium increased only slightly upon addition of the G-quadruplex. Molecular docking studies indicated that the naphthalimide derivatives were associated with the loop and groove of the human telomeric G-quadruplex via hydrophobic interactions. A hydrogen bond was formed between the imidazole group in compound 3 and the guanine residue DG16. The phosphate group from the G-quadruplex backbone pointed to the imidazolium moiety of 4ac, suggesting that the electrostatic interactions also played an important role. Being fluorescent, the cellular localization of 3 and 4ac could be conveniently tracked by fluorescence imaging. The results showed that compounds 4ac, which contained the imidazolium moiety, were mainly localized in the nucleus after 4.0 h of incubation, while compound 3 with the imidazole moiety was partially localized in the nucleus. The enhancement of the nuclear localization of 4ac may be attributed to the positive charge in 4ac and their higher DNA affinity. Based on the MTT assay results, it was concluded that compounds 4ac displayed much stronger cytotoxic activity against breast cancer cells than 3. Furthermore, compounds 4a and 4b selectively inhibited the A549 cells over normal human lung fibroblast MRC-5 cells, with high anticancer activity. These results indicated that the G-quadruplex binding affinity and anticancer activity of naphthalimide could be modulated by conjugation with the imidazole moiety.



Key wordsNaphthalimide      G-quadruplex      Anticancer drug      Imidazolium      Cytotoxicity     
Received: 30 October 2017      Published: 28 November 2017
MSC2000:  O642  
Fund:  the Natural Science Foundation of Shaanxi Province, China(2016JM2013);the National Natural Science Foundation of China(21073143);the NPU Foundation for Graduate Innovation(Z2017208)
Corresponding Authors: Zhize OU     E-mail: ouzhize@nwpu.edu.cn
Cite this article:

Yunyan GAO,Wenjiao CAI,Zhize OU,Tuotuo MA,Na YI,Zhiyuan LI. DNA Interactions and Cytotoxicity of Imidazole-Modified Naphthalimides. Acta Phys. -Chim. Sin., 2019, 35(2): 230-240.

URL:

http://www.whxb.pku.edu.cn/10.3866/PKU.WHXB201711281     OR     http://www.whxb.pku.edu.cn/Y2019/V35/I2/230

Fig 1 Synthetic route for the naphthalimide derivatives containing imidazole moiety.
Fig 2 UV-Vis titration of 3 (40 μmol·L?1) with (a) CT DNA and (b) Htelo G-quadruplex in Tris-HCl buffer (10 m mol·L?1, pH 7.4) containing 0.1 mol·L?1 KCl. The arrows indicate the changes upon addition of DNA. Insets: Plots of Dεap versus D.
Compound CT DNA Htelo DNA Selectivity a
Kα Red shift Kα Red shift
3 1.40 × 104 0 7.86 × 106 0 561
4a 5.31 × 104 0 4.27 × 106 0 80.2
4b 4.65 × 104 3 1.41 × 107 3 301
4c 1.24 × 105 10 9.22 × 106 4 74.4
Table 1 Association constant (Kα, L·mol?1) of naphthalimide derivatives with duplex CT DNA and Htelo G-quadruplex DNA determined by UV-Vis spectroscopy.
Fig 3 The fluorescence enhancement (F/F0) of naphthalimide derivatives upon addition of (a) CT DNA and (b) Htelo G-quadruplex.
Compound CT DNA a Htelo DNA b
3 2.99 10.0
4a 3.68 7.99
4b 3.59 9.90
4c 1.48 2.73
Table 2 Effects of double-stranded CT DNA and Htelo G-quadruplex DNA on the fluorescence enhancement (F/F0) of naphthalimide derivatives.
Fig 4 Effect of naphthalimide derivatives and EB on the relative viscosity of CT DNA (0.1 mmol·L?1) in Tris-HCl (10 mmol·L?1, pH 7.4) buffer containing 0.1 mol·L?1 KCl.
Fig 5 CD spectra of Htelo (20 μmol·L-1) inTrisHCl (10 mmol·L-1, pH 7.4) upon addition of 3, 4a–c (40 μmol·L-1) (a) in the presence of 0.1 mol·L-1·K+ and (b) in the absence of K+ .
Fig 6 Effect of naphthilimides 3, 4a–c on the melting temperature (Tm) of FHtelo G-quadruplex [FHtelo] = 0.2 μmol·L?1; [3] = [4a] = [4b] = [4c] = 1.0 μmol·L?1
Fig 7 Different views of the docked model of 3 (a, b), 4a (c, d) and 4c (e, f) with telomeric G-quadruplex DNA (PDB ID: 1KF1). The red dashed lines represent the hydrogen bonding or electrostatic interaction between naphthalimides and G-quadruplex.
Fig 8 Fluorescence images of A549 cells incubated with (a) 3, (d) 4b, and DAPI (b, e) for 4.0 h. (c) merged image of (a) and (b); (f) merged image of (d) and (e). [3] = [4b] = 10 μmol·L?1, [DAPI] = 5 μmol·L?1.
Compound A549 MRC-5 MRC-5IC50/A549IC50
3 15.3 ± 1.30 19.8 ± 2.1 1.29
4a 2.64 ± 0.42 7.93 ± 0.21 3.04
4b 2.23 ± 0.39 7.06 ± 0.89 3.16
4c 3.34 ± 0.53 3.63 ± 0.58 1.08
Mitonafide 3.78 ± 0.31 1.81 ± 0.15 0.47
Table 3 Data for the cytotoxicity (IC50, μmol·L?1) of naphthalimides against A549 and MRC-5 cells.
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