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Chemically-modified peptide nucleic acids: A versatile approach to complex molecular scaffolding and control of nucleic acid secondary architecture.

机译：化学修饰的肽核酸：复杂分子支架和核酸二级结构控制的通用方法。

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摘要

This dissertation covers the synthesis and study of peptide nucleic acids (PNAs), specifically, derivatives of PNA containing amine-bearing sidechains or cyclopentane portions. PNAs are non-natural nucleic acids that have far reaching potential in therapeutics and nucleic acid detection. Despite immense potential and widespread application, improving on the design and applications of PNA are areas of heavy research. This dissertation describes the successful synthesis of several PNA derivatives that show very promising binding properties while giving us unprecedented control of oligomer characteristics, both as scaffolds for complex molecular display and control of secondary structure.; The first chapter contains the necessary background into nucleic acids and their applications. The development of non-natural nucleic acids, specifically PNA, is described. The chapter also examines the precedent and logic used in the design of the PNA derivatives and experimental approach.; The second chapter pertains to the development of a chiral PNA derivative based on amine-containing "sidechains". The utility of this modification is that further functionality can be appended to each sidechain residue. As these sidechains are amenable to conjugation through amide bond-forming reactions during oligomer synthesis, very few starting PNA monomers need to be synthesized to achieve a wide variety of derivatized PNA residues. Our subsequent studies on the stability of this sidechain PNA demonstrated that the molecular recognition properties (affinity, selectivity) were enhanced for both DNA and RNA. Furthermore, we showed initial evidence that this modification strategy can be useful when designing light-up molecular probes, molecules that fluoresce only when bound to a target nucleic acid.; The third chapter explores a cyclic derivative of PNA in the context of non-Watson-Crick hydrogen bonding motifs. Despite the interest in non-standard PNA secondary structure, very few studies have focused on the effects that cyclic PNA or tethering can produce in non-duplex secondary structure. We discovered significant control over binding affinity and stoichiometry is possible through several entropy-reducing methods.; In the fourth and final chapter, I briefly summarize the dissertation and discuss future avenues of research in this area.
机译：本论文涵盖了肽核酸（PNA）的合成和研究，特别是包含含胺侧链或环戊烷部分的PNA的衍生物。 PNA是非天然核酸，在治疗和核酸检测中具有深远的潜力。尽管PNA具有巨大的潜力和广泛的应用，但对PNA的设计和应用进行改进仍是研究的重点。这篇论文描述了几种PNA衍生物的成功合成，这些衍生物显示出非常有前途的结合特性，同时为我们提供了前所未有的对低聚物特性的控制，既可以作为复杂分子展示的支架，也可以控制二级结构。第一章包含核酸及其应用的必要背景。描述了非天然核酸，特别是PNA的开发。本章还研究了PNA派生词的设计和实验方法中使用的先例和逻辑。第二章涉及基于含胺“侧链”的手性PNA衍生物的开发。该修饰的用途是可以将进一步的功能附加到每个侧链残基上。由于这些侧链易于在低聚物合成过程中通过酰胺键形成反应进行缀合，因此需要合成的起始PNA单体很少，以实现多种衍生的PNA残基。我们随后对该侧链PNA稳定性的研究表明，DNA和RNA的分子识别特性（亲和力，选择性）均得到增强。此外，我们显示出初步证据表明，这种修饰策略在设计发光分子探针时是有用的，该探针仅在与靶核酸结合时才发出荧光。第三章探讨了非沃森-克里克氢键基序中PNA的环状衍生物。尽管对非标准PNA二级结构感兴趣，但很少有研究集中在环状PNA或系链可在非双工二级结构中产生的影响。我们发现对结合亲和力和化学计量的显着控制可以通过几种减少熵的方法实现。在第四章也是最后一章中，我简要总结了论文并讨论了该领域的未来研究途径。

著录项

  • 作者

    Englund, Ethan Andrew.;

  • 作者单位

    Northwestern University.$bChemistry.;

  • 授予单位 Northwestern University.$bChemistry.;
  • 学科 Chemistry Organic.
  • 学位 Ph.D.
  • 年度 2007
  • 页码 204 p.
  • 总页数 204
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 有机化学;
  • 关键词

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