物理化学学报 >> 2015, Vol. 31 >> Issue (12): 2386-2394.doi: 10.3866/PKU.WHXB201510137

生物物理化学 上一篇    下一篇

炔基配体对2, 6-双(N-乙基苯并咪唑)吡啶炔基铂(Ⅱ)配合物与G-四链体作用及抗癌活性的影响

欧植泽*(),句宝龙,高云燕*(),王子超,黄干,钱一梦   

  • 收稿日期:2015-07-20 发布日期:2015-12-04
  • 通讯作者: 欧植泽,高云燕 E-mail:ouzhize@nwpu.edu.cn;gaoyunyan@nwpu.edu.cn
  • 基金资助:
    国家自然科学基金(21073143);教育部“春晖计划”基金(Z2009-1-71002, Z2009-1-71006);西北工业大学研究生创新种子基金(Z2015152);西北工业大学研究生创新基金

Alkynylplatinum(Ⅱ) 2, 6-Bis(N-ethylbenzimidazol-2'-yl)pyridine Complexes: Effect of Alkynyl Ligand on G-quadruplex Binding Properties and Anticancer Activity

Zhi-Ze. OU*(),Bao-Long. JU,Yun-Yan. GAO*(),Zi-Chao. WANG,Gan. HUANG,Yi-Meng. QIAN   

  • Received:2015-07-20 Published:2015-12-04
  • Contact: Zhi-Ze. OU,Yun-Yan. GAO E-mail:ouzhize@nwpu.edu.cn;gaoyunyan@nwpu.edu.cn
  • Supported by:
    the National Natural Science Foundation of China(21073143);“Chunhui Project” from the Ministry of Education ofChina(Z2009-1-71002, Z2009-1-71006);Graduate Starting Seed Fund of Northwestern Polytechnical University (NPU), China(Z2015152);NPU Foundation for Graduate Innovation, China

摘要:

合成了三种2, 6-双(N-乙基苯并咪唑)吡啶炔基铂(Ⅱ)配合物(2-4),其中配合物2的炔基配体为抗癌药物埃罗替尼.利用紫外-可见(UV-Vis)吸收光谱,圆二色(CD)光谱,荧光共振能量转移(FRET)等方法研究了铂(Ⅱ)配合物与人体端粒(Hetelo)和c-myc原癌基因(c-myc)G-四链体的相互作用.实验结果表明,所合成的铂配合物与G-四链体具有较强的相互作用(Ka > 106 L·mol-1),在无碱金属离子存在条件下能诱导G-四链体的形成.含苯乙炔基团的配合物2、3能使c-myc G-四链体的熔解温度上升24 ℃以上,而含丙炔基团的铂配合物4仅使c-mycG-四链体的熔解温度升高9.0 ℃,表明炔基结构对铂(Ⅱ)配合物与G-四连体的作用有较大影响.配合物2对人肺癌细胞A549的细胞毒性明显高于埃罗替尼及其他两种配合物3、4.

关键词: G-四链体, 铂(Ⅱ)配合物, 抗癌活性, DNA作用, 炔基配体

Abstract:

Three alkynylplatinum(Ⅱ)-2, 6-bis(N-ethylbenzimidazol-2'-yl)pyridine complexes 2-4 were synthesized and characterized. The alkynyl ligand in complex 2 is the anticancer drug erlotinib. The interactions between the Pt(Ⅱ) complexes and G-quadruplexes, including human telomeric (Hetelo) and cmyc oncogene (c-myc) quadruplexes, were investigated using UV-Vis spectroscopy, circular dichroism (CD), and fluorescence resonance energy transfer (FRET) melting assays. These studies show that the Pt(Ⅱ) complexes 2-4 have high affinities for G-quadruplexes (Ka > 106 L·mol-1), and can promote the formation of G-quadruplexes even in the absence of alkali cations. The Pt(Ⅱ) complexes 2 and 3, containing a phenylacetylene moiety, induce a high degree of stabilization of the c-myc G-quadruplex, with a melting temperature increase (ΔTm) of more than 24 ℃, but complex 4, containing a propyne moiety, only induces ΔTm of 9.0 ℃. These results indicate that the structure of the alkynyl ligand is important in the interactions between Pt(Ⅱ) complexes and G-quadruplexes. The cytotoxicity of complex 2 to the human adenocarcinoma A549 cell line is higher than those of complexes 3, 4, and erlotinib.

Key words: G-quadruplex, Platinum(Ⅱ) complex, Anticancer activity, DNA interaction, Alkynyl ligand

MSC2000: 

  • O642