Engineering hydrophilic/amphiphilic Vitamin B6-based super antioxidant dendrimers for controlling chronic inflammation

工程设计亲水性/两亲性维生素 B6 超级抗氧化树枝状聚合物，用于控制慢性炎症

• 批准号: 10515089
• 负责人: Choon Young Lee
• 金额: $ 42.63万
• 依托单位: CENTRAL MICHIGAN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10515089
• 关键词: Aftercare; Aldehydes; Alkynes; Amination; Anti-Inflammatory Agents; Antioxidants; Architecture; Area; Arthritis; Ascorbic Acid; Asthma; Atherosclerosis; Azides; Biological; Biological Assay; Biological Availability; CCL2 gene; Carbon; Catechols; Cell Survival; Cells; Chemicals; Chemistry; Chronic; Clinical Research; Copper; DNA; DNA Damage; Dendrimers; Diabetes Mellitus; Disease; Dose; Engineering; Ensure; Evaluation; Free Radical Scavenging; Free Radicals; Half-Life; Health; High Pressure Liquid Chromatography; Human; Human Pathology; Hybrids; Hydrogen Peroxide; Hydrophobicity; Hydroxyl Radical; In Vitro; Inflammation; Inflammation Mediators; Inflammatory Response; Interferons; Interleukin-1 beta; Interleukin-12; Interleukin-6; Ions; Iron; Life; Light; Lipopolysaccharides; Lipoproteins; Low-Density Lipoproteins; Malignant Neoplasms; Mass Spectrum Analysis; Mediator of activation protein; Membrane Lipids; Metals; Methods; Modeling; Molecular Sieve Chromatography; Molecular Structure; Molecular Weight; Monitor; Nature; Neurodegenerative Disorders; Outcome; Oxidative Stress; Pathogenesis; Pharmacology; Phase; Phenols; Polyacrylamide Gel Electrophoresis; Prevention; Production; Property; Protein Analysis; Pyridoxal; Pyridoxal Phosphate; Quercetin; Reactive Oxygen Species; Reporting; Research; Role; Solubility; Spectrum Analysis; Supplementation; Surface; System; TNF gene; Techniques; Testing; Therapeutic Agents; Toxic effect; Transition Elements; Vitamin B6; Vitamin E; Water; Water-Soluble Vitamin; Wine; Work; amphiphilicity; analytical method; aqueous; base; cell injury; chelation; cytokine; cytotoxicity; diphenyl; disorder prevention; gel electrophoresis; human disease; hydrophilicity; improved; innovation; macrophage; metal chelator; nano; novel; perhydroxyl radical; prevent; propargylamine; protective effect; public health relevance; water solubility

Title: Engineering hydrophilic/amphiphilic Vitamin B6-based super antioxidant dendrimers for controlling chronic inflammation Project Summary/Abstract Free radicals produced during chronic inflammation can damage cellular materials and cause oxidative stress, which can intensify pathogenesis of various irreversible human diseases. Many studies report that naturally occurring antioxidants such as vitamins C and E and quercetin are beneficial for prevention of a variety of human ailments including asthma and cancer, but some studies are contradictory. Many natural antioxidants in the presence of transition metal ions, like copper and iron, generate more free radicals (pro-oxidant effect). The pro-oxidant effect is more severe with antioxidants that can directly coordinate with the metal ions through their phenolic hydroxyl (OH) groups, such as catechol or gallol. We believe that this pro-oxidant action of antioxidants explains the detrimental health effects reported for antioxidant supplements in clinical studies. We previously synthesized large dendritic antioxidants with multiple phenolic units on the surface and interior with metal chelating capability. These dendritic antioxidants showed much higher antioxidant activities over naturally occurring popular antioxidants. For example, the dendrimer with 8 syringol units had 18-fold lower IC50 in the DPPH assay than that of vitamin C. More importantly, they are devoid of harmful pro-oxidant effects. We believed that the absence of pro-oxidant effects was achieved by entrapping metal ions within their interior as well as using hindered phenolic units whose OH do not chelate transition metal ions. A major drawback of the antioxidant dendrimers was their poor water-solubility. These antioxidants were highly effective in quenching organic radicals and protecting non-polar biomolecules such as membrane lipids and lipoproteins. However, their ability to quench water-soluble radicals such as OH· was limited. Various attempts to increase the aqueous solubility of these compounds by incorporation of cores and branches rich in polar groups were unsuccessful. In this proposal, we plan to develop a new class of hydrophilic/amphiphilic antioxidant dendrimers with built-in potent antioxidant activity as well as metal chelating ability by synthesis and assembly of pie-shaped dendritic segments known as dendrons (convergent method). A dendron with metal chelating ability will be synthesized and its surface will be modified with three different classes of building blocks (BBs) that are hydrophilic, hydrophobic, and amphiphilic. Water-soluble Vitamin B6 molecules (pyridoxal and pyridoxal-5’-phosphate) will be used to form hydrophilic BBs and syringaldehyde, a hydrophobic BB. The focal point of dendrons will be attached to a chemical carrying either an azido or alkynyl group. Attachment of the properly matched dendrons via their focal points would yield hydrophilic/amphiphilic dendrimers with potent antioxidant activities and devoid of any pro-oxidant actions. High potency will be achieved by attaching numerous hindered antioxidant units to the surface of the dendron. The efficient metal chelation that helps prevent the pro-oxidant effect will be achieved by embedding the N and O atoms to the interior of dendron. Conjugation of BBs to the dendron surface and dendrons to dendrons will be done by “alkyne-azide click” chemistry. The synthesized dendrimers will be tested for antioxidant activities (using chemical assays and the biomolecules DNA and LDL) and pro-oxidant potential (using DNA). Cell toxicity will be assessed by the MTT assay. Anti-inflammatory action on cytokine production will also be evaluated using RAW 264.7 macrophage cells. Potent hydrophilic/amphiphilic antioxidant dendrimers free from pro-oxidant effects are potential therapeutic agents for controlling chronic inflammation, and thus preventing/treating diseases strongly associated with oxidative stress caused by free radicals. The availability of these antioxidants will also help resolve the controversy associated with antioxidant supplementation in disease prevention/treatment.

标题：工程设计基于亲水性/两亲性维生素B6的超级抗氧化剂树枝状聚合物 控制慢性炎症 项目总结/摘要 慢性炎症过程中产生的自由基会损害细胞物质并引起氧化应激， 从而加剧人类各种不可逆转疾病的发病机制。许多研究报告说， 存在的抗氧化剂，如维生素C和E以及槲皮素， 包括哮喘和癌症在内的人类疾病，但一些研究是矛盾的。许多天然抗氧化剂， 过渡金属离子如铜和铁的存在产生更多的自由基（促氧化剂效应）。的 促氧化剂效应对于可以通过其与金属离子直接配位的抗氧化剂更严重。 酚羟基（OH）基团，如邻苯二酚或没食子酸。我们认为，这种促氧化剂的作用， 抗氧化剂解释了临床研究中报道的抗氧化剂补充剂对健康的有害影响。我们 先前合成的在表面和内部具有多个酚单元的大树枝状抗氧化剂， 金属螯合能力。这些树枝状的抗氧化剂显示出更高的抗氧化活性， 天然抗氧化剂例如，具有8个藜芦醇单元的树枝状聚合物具有低18倍的 DPPH法中的IC 50高于维生素C。更重要的是，它们不含有害的促氧化剂 方面的影响.我们认为，不存在促氧化剂作用是通过将金属离子截留在它们的分子内来实现的。 以及使用其OH不螯合过渡金属离子的受阻酚单元。一个主要 抗氧化剂树枝状聚合物的缺点是它们的水溶性差。这些抗氧化剂是高度 有效地猝灭有机自由基和保护非极性生物分子如膜脂， 脂蛋白然而，它们淬灭水溶性自由基如OH·的能力有限。各种尝试 通过引入富含极性的核和支链来增加这些化合物的水溶性 团体没有成功。在这个提议中，我们计划开发一类新的亲水/两亲性聚合物。 通过合成具有内在有效抗氧化活性以及金属螯合能力的抗氧化剂树枝状聚合物 以及称为树枝状分子的饼形树枝状片段的组装（收敛方法）。一种树枝， 合成了具有金属螯合能力的复合材料，并对其表面进行了三种不同结构的改性 亲水性、疏水性和两亲性嵌段（BB）。水溶性维生素B6分子（吡哆醛 和吡哆醛-5’-磷酸）将用于形成亲水性BB和疏水性BB--双乙醛。的 树枝化基元的焦点将连接到带有叠氮基或炔基的化学物质上。附接 通过它们的焦点适当匹配的树枝状分子将产生亲水性/两亲性树枝状聚合物 具有抗氧化活性且没有任何促氧化作用。高效力将通过连接 许多受阻的抗氧化剂单元到树枝化基元的表面。有效的金属螯合作用 通过将N和O原子嵌入到树枝状分子的内部来防止促氧化作用。 通过“炔-叠氮化物点击”将BB缀合至树枝化基元表面和树枝化基元缀合至树枝化基元。 化学.将测试合成的树枝状聚合物的抗氧化活性（使用化学测定和生物活性测定）。 生物分子DNA和LDL）和促氧化剂潜力（使用DNA）。将通过MTT法评估细胞毒性 比色法还将使用RAW 264.7巨噬细胞评价对细胞因子产生的抗炎作用 细胞有效的亲水性/两亲性抗氧化剂树枝状聚合物无促氧化作用是潜在的 用于控制慢性炎症并因此强烈预防/治疗疾病的治疗剂， 与自由基引起的氧化应激有关。这些抗氧化剂的可用性也将有助于 解决与疾病预防/治疗中的抗氧化剂补充相关的争议。