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首页> 外文期刊>RSC Advances >Molecular recognition of parallel quadruplex [d-(TTGGGGT)](4) by mitoxantrone: binding with 1: 4 stoichiometry leads to telomerase inhibition
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Molecular recognition of parallel quadruplex [d-(TTGGGGT)](4) by mitoxantrone: binding with 1: 4 stoichiometry leads to telomerase inhibition

机译：用米洛酮的平行Quadreplex [D-（Ttggggggt）]（4）的分子识别：与1：4的结合，化学计量导致端粒酶抑制

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摘要

The interaction of mitoxantrone (MTX), an anticancer drug, with parallel stranded tetra-molecular G-quadruplex DNA [d-(TTGGGGT)](4) has been studied using Surface Plasmon Resonance (SPR), thermal melting profiles, absorption, nuclear magnetic resonance and Circular Dichroism (CD) spectroscopy. Mitoxantrone binds to G-quadruplex DNA with the affinity constant K-A similar to 3 x 10(4) M-1 and the binding stoichiometry of the mitoxantrone : DNA quadruplex complex is found to be 4 : 1. The DNA melting (T-m) experiments show that binding leads to an increase in T-m indicating the thermal stabilization of DNA. T-m increases with D/N, that is, the ratio of added mole equivalents of mitoxantrone (D) to DNA (N) and saturates at D/N = 4.0 yielding total Delta T-m = 26 degrees C. Proton and phosphorus-31 chemical shifts show that the base pairs of DNA do not open to allow intercalation of a mitoxantrone chromophore. The 2D NOESY spectra reveal that mitoxantrone binds as a stacked dimer having head to tail (anti-parallel) orientation at two opposite ends externally to the DNA quadruplex. CD spectra show the induced CD band of mitoxantrone having exciton splitting at 630-690 nm. The TRAP assay gives IC50 similar to 2 mu M for inhibition of telomerase by mitoxantrone, which may be attributed to thermal stabilization of the DNA quadruplex. The present study suggests that a dimer formed by stacking of two mitoxantrone molecules might provide highly specific molecular recognition between ligands and a parallel stranded G-quadruplex and hence serve as a platform for rational design of new G-quadruplex groove binders.
机译：采用表面等离子体共振（SPR），热熔型材，吸收，核，研究了抗癌酮（MTX），抗癌药物，抗癌药物，抗癌药物，抗癌药物，抗癌药物，抗癌药物，抗癌药物，抗癌药物]（4）。磁共振和圆形二色性（CD）光谱。 Mitoxantrone与具有类似3×10（4）m-1的亲和力常数Ka与G-Quadrepled DNA结合，并发现米洛烷酮的结合化学计量：DNA Quadreplex复合物是4：1。DNA熔化（TM）实验表明该结合导致TM的增加表明DNA的热稳定。 TM随着D / N的增加，即米洛烷酮（D）的添加摩尔当量与DNA（N）的比率，并在D / N = 4.0下饱和，得到总δTM= 26℃，质子和磷-31化学变换表明DNA碱基对不打开以允许嵌入米氧基酮发色团。 2D NOESY光谱显示米曲蒽醌作为堆叠二聚体结合，其具有头部到尾部（抗平行）取向的两个相对的两端，直到DNA四边形。 CD光谱显示诱导的含有激子分裂的乳氧化酮的CD条带分裂在630-690nm。捕集试验使IC50类似于含有Mitoxantrone的端粒酶抑制的2μm，这可能归因于DNA QuadRuple的热稳定。本研究表明，通过堆叠两种丝唑烷酮分子形成的二聚体可以在配体和平行的链状G-quadreple之间提供高度特异性的分子识别，并且因此用作新的G-四边形槽粘合剂的合理设计的平台。

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  • 来源
    《RSC Advances》 |2016年第75期|共10页
  • 作者

    Pradeep Tarikere Palakshan; Tripathi Sweta; Barthwal Ritu;

  • 作者单位

    Indian Inst Technol Roorkee Dept Biotechnol Roorkee 247667 Uttar Pradesh India;

    Indian Inst Technol Roorkee Dept Biotechnol Roorkee 247667 Uttar Pradesh India;

    Indian Inst Technol Roorkee Dept Biotechnol Roorkee 247667 Uttar Pradesh India;

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  • 正文语种 eng
  • 中图分类 化学;
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