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首页> 外文学位 >Cleavage of an RNA analog by mononuclear zinc(II) macrocyclic complexes and metal ion and metallodrug interactions with deoxyribonucleic acids.
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Cleavage of an RNA analog by mononuclear zinc(II) macrocyclic complexes and metal ion and metallodrug interactions with deoxyribonucleic acids.

机译：通过单核锌（II）大环络合物以及与脱氧核糖核酸的金属离子和金属药物相互作用来切割RNA类似物。

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摘要

A series of five mononuclear Zn(II) macrocycle complexes were designed and synthesized for the catalyzed cleavage of the RNA analog, 2-hydroxylpropyl-4-nitrophenyl phosphate (HpPNP). The Zn(II) macrocylces include Zn(II) 1,4,7,10-tetraazacyclododecane (Zn(1)), Zn(II) 1-oxa-4,7,10-triazacyclododecane (Zn(2)), Zn(II) 1,5,9-triazacyclododecane ( Zn(3)), Zn(II) 1-hydroxyethyl-1,4,7-triazacyclononane (Zn(4)) and Zn(II) N'-methyl-1-oxa-4,7,10-triazacyclododecane (Zn(5)). The second-order rate constants were measured for each of the catalysts as a function of pH, where a downward break is centered at the pKa for the zinc aqua ligand. The macrocyclic Zn(II) complexes were compared to the free ion, Zn(H2O) 62+, and found to only moderately increase and decrease the transition state stabilization energy. Inhibition studies at pH = 7.6, involving a ground state phosphodiester mimic (DEP), a transition state mimic (MP2-), a coordination probe (Ox2-) and the nucleobase uridine ( U) were used to examine various properties of the Zn(II) complexes. All of the Zn(II) macrocycles displayed weak binding to DEP, while Zn(4) exhibited the weakest binding to MP2- and U, which is attributed to its inability to bind anions tightly at lower pH. Zn(1) displayed weak inhibition to the known bidentate chelator, Ox2-, which suggests that it cannot accommodate as many substrate binding sites or aqua ligands. The pH-Inhibition profile of Zn(2) and MP2- shows that weaker binding to the inhibitor is shown at higher pH because of competition with hydroxide anions, which suggests that the aqua form of the catalyst is in fact the active species in the phosphodiester catalysis of HpPNP.;The interactions of metal ions and a metallodrug with various structures of DNA were studied. Lanthanide luminescence and lanthanide induced shifts of 1H NMR were examined to determine the location of metal ion and metallodrug binding within DNA. The studies shows that weak, non-specific binding is observed for Eu(III) and Eu(CPFX) to single stranded pentamers containing the same nucleobase. Eu(III) and Ce(III) binding to long, double stranded duplex structures were much stronger and the ions remained hydrated. The steady-state luminescence excitation spectrum of Eu(CPFX) show that all of the Eu(CPFX)2 is converted to the Eu(CPFX) species when interacting with the duplex DNA. The weakest interactions of Eu(CPFX) are observed with d(AATT)6. Binding within the Dickerson-Drew dodecamer (5'-GCGCAATTGCGC-3') show that Ce(CPFX) prefers binding in the dodecamer GCGC domains. Thymine hairpins were also studied, which display specific Eu(III) and Eu(CPFX) binding that is accompanied by partial dehydration of inner sphere aqua ligands. Based on the lanthanide induced shifts observed in the NMR spectrum, Ce(III) shows greater selectivity for the T3 and T4 hairpin loops, whereas the Ce(CPFX) displays binding to the 5'-GCGC-3' stem and weaker specific binding to the thymine hairpin. The ciprofloxacin ligand appears to block deeper penetration of the metallodrug complex into the hairpin structure. The Ce(CPFX) induces shifts of all the thymine residues of the T4 hairpin suggesting a less specific interaction takes place with the Ce(CPFX) than Ce(III).
机译：设计并合成了一系列五个单核Zn（II）大环络合物，用于催化催化类似物2-羟基丙基-4-硝基苯基磷酸酯（HpPNP）的裂解。 Zn（II）大环包括Zn（II）1,4,7,10-四氮杂十二烷（Zn（1）），Zn（II）1-oxa-4,7,10-三氮杂十二烷（Zn（2）），Zn （II）1,5,9-三氮杂环十二烷（Zn（3）），Zn（II）1-羟乙基-1,4,7-三氮杂环壬烷（Zn（4））和Zn（II）N'-甲基-1- oxa-4,7,10-三氮杂环十二烷（Zn（5））。测量每种催化剂的二级速率常数作为pH的函数，其中向下断裂的中心是锌水配体的pKa。将大环Zn（II）络合物与自由离子Zn（H2O）62+进行比较，发现它们仅适度增加和降低了过渡态稳定能。在pH = 7.6时进行的抑制研究涉及基态磷酸二酯模拟物（DEP），过渡态模拟物（MP2-），配位探针（Ox2-）和核碱基尿苷（U），用于研究Zn（ II）复合物。所有的Zn（II）大环都显示出与DEP的弱结合，而Zn（4）显示出与MP2-和U的结合最弱，这归因于其在较低pH下无法紧密结合阴离子。 Zn（1）对已知的双齿螯合剂Ox2-表现出微弱的抑制作用，这表明它不能容纳许多底物结合位点或aqua配体。 Zn（2）和MP2-的pH抑制曲线表明，由于与氢氧根阴离子的竞争，在较高的pH值下与抑制剂的结合较弱，这表明催化剂的水合形式实际上是磷酸二酯中的活性物质；研究了金属离子与金属药物与DNA的各种结构的相互作用。检查镧系元素的发光和镧系元素引起的1 H NMR位移，以确定DNA中金属离子和金属药物结合的位置。研究表明，对于Eu（III）和Eu（CPFX），与包含相同核碱基的单链五聚体存在弱的非特异性结合。与长双链双链体结构结合的Eu（III）和Ce（III）强得多，并且离子保持水合状态。 Eu（CPFX）的稳态发光激发光谱表明，当与双链DNA相互作用时，所有Eu（CPFX）2都转化为Eu（CPFX）物种。 Eu（CPFX）与d（AATT）6的相互作用最弱。 Dickerson-Drew十二聚体（5'-GCGCAATTGCGC-3'）中的结合表明Ce（CPFX）倾向于十二聚体GCGC域中的结合。还研究了胸腺嘧啶发夹，它们显示出特定的Eu（III）和Eu（CPFX）结合，并伴有内球水配体的部分脱水。根据在NMR光谱中观察到的镧系元素引起的位移，Ce（III）对T3和T4发夹环显示出更高的选择性，而Ce（CPFX）显示与5'-GCGC-3'茎的结合并且对C'（CPFX）的特异性结合较弱胸腺嘧啶发夹。环丙沙星配体似乎阻止了金属药物复合物更深地渗透入发夹结构。 Ce（CPFX）诱导T4发夹的所有胸腺嘧啶残基转移，这表明与Ce（CPFX）的相互作用比Ce（III）少。

著录项

  • 作者

    Mathews, Ryan.;

  • 作者单位

    State University of New York at Buffalo.;

  • 授予单位 State University of New York at Buffalo.;
  • 学科 Chemistry Analytical.;Chemistry Pharmaceutical.;Chemistry Inorganic.
  • 学位 Ph.D.
  • 年度 2008
  • 页码 254 p.
  • 总页数 254
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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