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：工程亲水/两亲维生素 B6 基超级抗氧化剂树枝状聚合物 控制慢性炎症 项目概要/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， 许多研究表明，这会加剧各种不可逆转的人类疾病的发病机制。 维生素 C、E 和槲皮素等抗氧化剂有助于预防各种疾病的发生 人类疾病包括哮喘和癌症，但一些研究与许多天然抗氧化剂相矛盾。 过渡金属离子（如铜和铁）的存在会产生更多自由基（促氧化作用）。 抗氧化剂的促氧化作用更为严重，因为抗氧化剂可以通过其自身的作用直接与金属离子配位。 酚羟基（OH）基团，例如儿茶酚或没食子醇，我们相信这种促氧化作用。 抗氧化剂解释了临床研究中报告的抗氧化剂补充剂对疼痛健康的影响。 先前合成的大树枝状抗氧化剂，其表面和内部具有多个酚单元 这些树枝状抗氧化剂表现出更高的抗氧化活性。 例如，含有 8 个丁香醇单元的树枝状大分子的抗氧化剂含量低 18 倍。 DPPH 测定中的 IC50 高于维生素 C。更重要的是，它们不含有害的促氧化剂 我们认为，促氧化作用的缺失是通过将金属离子捕获在其内部来实现的。 内部以及使用受阻酚单元，其 OH 不螯合过渡金属离子 A 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的。 有效猝灭有机自由基并保护非极性生物分子，如膜脂和 然而，它们淬灭水溶性自由基（例如OH·）的能力是有限的。 通过掺入富含极性的核和支链来增加这些化合物的水溶性 在这个提案中，我们计划开发一类新的亲水/两亲性基团。 合成的抗氧化剂树枝状聚合物具有强大的抗氧化活性以及金属螯合能力 以及称为树突的饼形树突片段的组装（收敛方法）。 将合成金属螯合能力，并用三种不同类别的建筑对其表面进行改性 亲水性、疏水性和两亲性嵌段（BB）。 和吡哆醛-5'-磷酸）将用于形成亲水性 BB 和丁香醛（疏水性 BB）。 树枝状分子的焦点将附着在带有叠氮基或炔基的化学物质上。 通过其焦点正确匹配的树枝状大分子将产生具有有效作用的亲水性/两亲性树枝状聚合物 抗氧化活性和无任何促氧化作用将通过附着来实现。 树突表面有许多受阻抗氧化剂单位，有助于有效的金属螯合。 通过将N和O原子嵌入树枝状分子的内部来实现防止促氧化作用。 BB与树突表面以及树突与树突的共轭将通过“炔-叠氮化物点击”完成 合成的树枝状聚合物将进行抗氧化活性测试（使用化学测定和 生物分子 DNA 和 LDL）和促氧化潜力（使用 DNA）将通过 MTT 进行评估。 还将使用 RAW 264.7 巨噬细胞评估对细胞因子产生的抗炎作用。 不含促氧化作用的有效亲水性/两亲性抗氧化剂树枝状聚合物是潜在的。 控制慢性炎症、从而强力预防/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所帮助。 解决与疾病预防/治疗中补充抗氧化剂相关的争议。