咪唑修饰萘酰亚胺与DNA的作用及其细胞毒性
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摘要
设计合成了咪唑及其烷基化咪唑阳离子基团修饰的萘酰亚胺衍生物。利用紫外-可见吸收光谱、荧光光谱、圆二色谱和荧光共振能量转移等方法研究了它们与小牛胸腺DNA(CT DNA)和G-四链体DNA的相互作用。这些化合物对端粒DNA序列的G-四链体有很高的结合能力(K_α>4×10~6 L·mol~(-1)),并能够稳定G-四链体。DNA粘度实验结果表明萘酰亚胺衍生物与CT DNA通过插入作用结合。Autodock分子对接模拟结果表明这些化合物通过疏水作用、静电作用或氢键等方式与人体端粒G-四链体的loop和沟槽部分结合。咪唑阳离子基团修饰的萘酰亚胺衍生物4a–c能够定位于细胞核,对肺癌细胞的细胞毒性要高于咪唑基团修饰的萘酰亚胺衍生物3。化合物4a和4b对肺癌细胞A549的细胞毒性明显高于正常人胚肺成纤维细胞MRC-5,表现出良好的抗癌活性。
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 naphthalimideimidazole conjugate(3)and its alkylated derivatives(4a–c)were synthesized,and characterized by ~1H NMR,~(13)C 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 withimidazolium 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(K_a>4×10~6 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.FRETresults indicated that the compounds 3 and 4a–c stabilized the structure of the telomeric G-quadruplex by increasing its melting temperature by 5.8,10.7,8.4,and 7.8°C,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 4a–c)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 of4a–c,suggesting that the electrostatic interactions also played an important role.Being fluorescent,the cellular localization of 3 and 4a–c could be conveniently tracked by fluorescence imaging.The results showed that compounds 4a–c,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 4a–c may be attributed to the positive charge in 4a–c and their higher DNA affinity.Based on the MTT assay results,it was concluded that compounds 4a–c 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.
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 naphthalimideimidazole conjugate(3)and its alkylated derivatives(4a–c)were synthesized,and characterized by ~1H NMR,~(13)C 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 withimidazolium 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(K_a>4×10~6 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.FRETresults indicated that the compounds 3 and 4a–c stabilized the structure of the telomeric G-quadruplex by increasing its melting temperature by 5.8,10.7,8.4,and 7.8°C,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 4a–c)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 of4a–c,suggesting that the electrostatic interactions also played an important role.Being fluorescent,the cellular localization of 3 and 4a–c could be conveniently tracked by fluorescence imaging.The results showed that compounds 4a–c,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 4a–c may be attributed to the positive charge in 4a–c and their higher DNA affinity.Based on the MTT assay results,it was concluded that compounds 4a–c 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.
引文
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