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首页> 外文学位 >Synthesis and biological evaluation of 2-(2'-hydroxyphenyl) benzoxazole analogs of UK-1, and G-quadruplex selectivity of perylene diimide compounds.
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Synthesis and biological evaluation of 2-(2'-hydroxyphenyl) benzoxazole analogs of UK-1, and G-quadruplex selectivity of perylene diimide compounds.

机译：UK-1的2-（2'-羟苯基）苯并恶唑类似物的合成和生物学评估，以及di二酰亚胺化合物的G-四联体选择性。

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摘要

A great number of pharmaceutical drugs target nucleic acids. However, drug-DNA interactions can be region non-specific and lead to undesired side effects. Understanding the mechanisms that regulate drug-DNA binding can help in the design of potent and selective therapeutic agents with fewer deleterious side effects. The present investigation explores the metal-mediated DNA binding of a group of 2-(2-hydroxyphenyl)benzoxazole (HPB) ligands and the aggregation dependant G-quadruplex selectivity of a series of perylene tetracarboxylic acid diimides (PTCDI) compounds.; HPB ligands are simplified analogs of the bis-benzoxazole natural product UK-1. This compound is able to inhibit cell growth of various tumor cell lines, bind divalent cations, and interact with DNA in a metal dependant fashion. The HPB moiety present in UK-1 was identified as relevant for its metal ion binding and biological properties. For this work, novel HPB ligands were synthesized with different substitutions at the C4 or C7 position. Their ability to bind metal ions and DNA was evaluated and their cytotoxicity was assessed in multiple cancer cell lines. The ligands bound to Cu2+ with the highest affinity among metals studied. Consequently, Cu2+ promoted the most dramatic increase in DNA binding and affected the ligand's cellular cytotoxicity.; The second project focused on targeting four-stranded structures called G-quadruplexes, which can form in G-rich nucleic acid sequences. Compounds that stabilize these structures may inhibit nucleic acid-processing enzymes such as telomerase and potentially act as anti-cancer agents. PIPER is a PTCDI that is particularly selective for G-quadruplex DNA versus duplex DNA under conditions in which it forms aggregates. This work investigated ligand aggregation in a series of PIPER analogs with different structural features under high and low salt buffers, changes in pH, metal binding and temperature changes. A negatively charged analog was determined to form metal-mediated aggregates while novel thermophilic mediated aggregation was discovered for an analog with methoxyethoxymethyl groups. The ability of these ligands to bind different DNA structures was evaluated under aggregating and non-aggregating conditions. This study supports the idea that ligand aggregation increases their quadruplex selectivity and decreases double-stranded DNA binding.
机译：许多药物靶向核酸。但是，药物与DNA的相互作用可能是区域非特异性的，并导致不良副作用。了解调节药物与DNA结合的机制可以帮助设计具有较少有害副作用的有效和选择性治疗剂。本研究探索了一组2-（2-羟苯基）苯并恶唑（HPB）配体的金属介导的DNA结合以及一系列per四羧酸二酰亚胺（PTCDI）化合物的依赖于聚集的G-四链体选择性。 HPB配体是双苯并恶唑天然产物UK-1的简化类似物。该化合物能够抑制多种肿瘤细胞系的细胞生长，结合二价阳离子，并以金属依赖性方式与DNA相互作用。 UK-1中存在的HPB部分被确定与其金属离子结合和生物学特性有关。对于这项工作，合成了新颖的HPB配体，在C4或C7位置具有不同的取代基。评估了它们结合金属离子和DNA的能力，并评估了它们在多种癌细胞系中的细胞毒性。在研究的金属中，配体以最高的亲和力与Cu2 +结合。因此，Cu2 +促进了DNA结合的最大增加，并影响了配体的细胞毒性。第二个项目的重点是靶向称为G-四链体的四链结构，该结构可在富含G的核酸序列中形成。稳定这些结构的化合物可能会抑制核酸加工酶，例如端粒酶，并有可能充当抗癌剂。 PIPER是PTCDI，在形成聚集体的条件下，它对G-四链体DNA相对于双链体DNA具有特别的选择性。这项工作研究了在高盐和低盐缓冲液，pH值变化，金属结合和温度变化下一系列具有不同结构特征的PIPER类似物中的配体聚集。确定带负电荷的类似物形成金属介导的聚集体，而发现具有甲氧基乙氧基甲基的类似物的新型嗜热介导的聚集。在聚集和非聚集条件下评估这些配体结合不同DNA结构的能力。该研究支持配体聚集增加其四链体选择性并减少双链DNA结合的想法。

著录项

  • 作者

    McKee, Mireya Loreley.;

  • 作者单位

    The University of Texas at Austin.$bDepartment of Chemistry and Biochemistry.;

  • 授予单位 The University of Texas at Austin.$bDepartment of Chemistry and Biochemistry.;
  • 学科 Chemistry Biochemistry.
  • 学位 Ph.D.
  • 年度 2007
  • 页码 240 p.
  • 总页数 240
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 生物化学;
  • 关键词

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