Synthesis of 3-hydroxy-4-pyridinone hexadentate chelators, and biophysical evaluation of their affinity towards lipid bilayers

IF 4.5 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Bioorganic Chemistry Pub Date : 2024-09-05 DOI:10.1016/j.bioorg.2024.107806

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Abstract

Iron is an essential micronutrient for almost every living organism, namely pathogenic bacteria. In an infection scenario, host-pathogen competitive relationships for the element are present and Fe withholding is a well known response of the host. Also, bacterial resistance is a major concern that can compromise public health and the WHO underlines an urgent need to search for new pharmaceutical ingredients or strategies to fight opportunistic bacteria. Iron metabolism, and in particular, deprivation is a strategy that currently constitutes another option to fight bacterial infection.

In this work we report the synthesis of a new hexadentate chelator with enhanced hydrophilicity (MRHT) and the improved synthesis of two other chelators. The affinity towards charged and non-charged phospholipid bilayers was evaluated for three hexadentate chelators: MRHT, CP256 and RH8b using NMR and EPR spectroscopies. The results revealed that these structures, bearing 3,4-HPO units have a high affinity towards the hydrophilic region of the phospholipid bilayer. From the three hexadentate chelators, MRHT stood out, especially for liposomes with a charged surface, suggesting that this molecule could more efficiently compete with natural siderophores, creating an iron gradient near bacteria organisms.

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3-hydroxy-4-pyridinone hexadentate chelators 的合成及其对脂质双分子层亲和力的生物物理评估

铁是几乎所有生物（即病原菌）都必需的微量营养元素。在感染情况下，宿主和病原体之间存在着对铁元素的竞争关系，扣留铁元素是宿主的一种众所周知的反应。此外，细菌的抗药性也是一个令人担忧的重大问题，它可能危及公共卫生，世界卫生组织强调迫切需要寻找新的药物成分或策略来对抗机会性细菌。在这项工作中，我们报告了一种具有增强亲水性的新型六价螯合剂（MRHT）的合成情况，以及另外两种螯合剂的改进合成情况。我们评估了三种六价螯合剂对带电和不带电磷脂双分子层的亲和力：使用核磁共振和 EPR 光谱评估了 MRHT、CP256 和 RH8b 这三种六价螯合剂对带电和不带电磷脂双分子层的亲和力。结果表明，这些含有 3,4-HPO 单元的结构对磷脂双分子层的亲水区域具有很高的亲和力。在这三种六价螯合剂中，MRHT脱颖而出，尤其是对表面带电的脂质体而言，这表明该分子能更有效地与天然嗜铁离子竞争，在细菌生物体附近形成铁梯度。

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来源期刊

Bioorganic Chemistry 生物-生化与分子生物学

CiteScore

9.70

自引率

3.90%

发文量

679

审稿时长

31 days

期刊介绍： Bioorganic Chemistry publishes research that addresses biological questions at the molecular level, using organic chemistry and principles of physical organic chemistry. The scope of the journal covers a range of topics at the organic chemistry-biology interface, including: enzyme catalysis, biotransformation and enzyme inhibition; nucleic acids chemistry; medicinal chemistry; natural product chemistry, natural product synthesis and natural product biosynthesis; antimicrobial agents; lipid and peptide chemistry; biophysical chemistry; biological probes; bio-orthogonal chemistry and biomimetic chemistry. For manuscripts dealing with synthetic bioactive compounds, the Journal requires that the molecular target of the compounds described must be known, and must be demonstrated experimentally in the manuscript. For studies involving natural products, if the molecular target is unknown, some data beyond simple cell-based toxicity studies to provide insight into the mechanism of action is required. Studies supported by molecular docking are welcome, but must be supported by experimental data. The Journal does not consider manuscripts that are purely theoretical or computational in nature. The Journal publishes regular articles, short communications and reviews. Reviews are normally invited by Editors or Editorial Board members. Authors of unsolicited reviews should first contact an Editor or Editorial Board member to determine whether the proposed article is within the scope of the Journal.