Synthesis of atypical carotenoids: self-preserving inhibitors of lipid peroxidati

非典型类胡萝卜素的合成：脂质过氧化物的自我保护抑制剂

• 批准号: 8197629
• 负责人: Martin D Burke
• 金额: $ 29.74万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-01 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8197629
• 关键词: Address; Age related macular degeneration; Antioxidants; Arthritis; Asthma; Atherosclerosis; Attenuated; Biochemical; Biological Factors; Carotene; Carotenoids; Cell membrane; Cells; Chemicals; Clinical; Clinical Trials; Collection; Combinatorial Synthesis; Communities; Complex; Conduct Clinical Trials; Coupling; Development; Diabetes Mellitus; Disease; Employee Strikes; Foundations; Functional disorder; Future; Generations; Goals; Health; Human; In Vitro; Investigation; Knowledge; Lead; Letters; Lipid Bilayers; Lipid Peroxidation; Lipids; Liposomes; Lutein; Macular degeneration; Malignant Neoplasms; Malignant neoplasm of lung; Membrane; Membrane Lipids; Methods; Modification; Neurodegenerative Disorders; Oxygen; Phospholipids; Plants; Polyenes; Preparation; Principal Investigator; Process; Property; Publications; Reactive Oxygen Species; Reperfusion Injury; Research; Rheumatoid Arthritis; Role; Route; Safety; Screening procedure; Series; Structure; Structure-Activity Relationship; Testing; Therapeutic Agents; Time; Veins; analog; astaxanthine; base; combinatorial chemistry; design; flexibility; heart disease prevention; high throughput screening; human disease; improved; in vivo; inhibitor/antagonist; interest; lipid peroxidation inhibitor; microorganism; novel; novel therapeutics; oxidative damage; peroxidation; pre-clinical; programs; protective effect; small molecule; zeaxanthin

DESCRIPTION (provided by applicant): Project Summary Synthesis of atypical carotenoids: self-preserving inhibitors of lipid peroxidation Small molecules that safely and effectively inhibit the peroxidation of lipid bilayers stand to substantially advance the treatment of many prevalent human diseases, including atherosclerosis, cancer, macular degeneration, and arthritis. However, most of the known O antilipoperoxidants have important limitations. Me Me O Me H HO Me For example, typical carotenoids such as O astaxanthin have a strong propensity for self- Me HO Me peridinin (1) Me OAc destructive interactions with reactive oxygen Me species, which limits the lifetime of the lipid O protective effect and leads to the generation of HO Me Me harmful carotenoid breakdown products. In contrast, there are several recently discovered Me Me Me Me OH "atypical" carotenoids that have the potential Me for exceptional antilipoperoxidant activities via Me O synechoxanthin (2) self-preserving mechanisms of action. Specifically, this research program will develop O highly efficient and flexible syntheses of the HO O O O Me atypical carotenoids peridinin (1), HO O Me synechoxanthin (2), and di-[(6-O-oleoyl-2-D- HO Me Me Me Me glucopyranosyl)oxy]-astaxanthin (3), execute Me Me Me Me systematic structure/function studies to Me O O OO OH understand their unique antilipoperoxidant OH profiles, and extensively optimize their Me O OH activities via iterative cycles of rationally- guided combinatorial synthesis and high- di-[(6-O-oleoyl-!-D-glucopyranosyl)oxy]-astaxanthin (3) throughput screening. PHS 398/2590 (Rev. 05/01) Page Continuation Format Page PUBLIC HEALTH RELEVANCE: Project Narrative Synthesis of atypical carotenoids: self-preserving inhibitors of lipid peroxidation Several recently discovered natural products have the potential to serve as powerful antioxidants inside cell membranes, and therefore may lead to improved treatments for a variety of prevalent diseases, including atherosclerosis, cancer, and arthritis. In contrast to related antioxidants that have been studied previously, these new compounds do not self-destruct as they protect the membrane from oxidative damage, which is critical for maximizing efficacy and safety. This research program will lead to the efficient synthesis, detailed study, and extensive optimization of these novel "self-preserving" antioxidants. PHS 398/2590 (Rev. 05/01) Page Continuation Format Page

描述(申请人提供)：项目摘要非典型类胡萝卜素的合成：自保的脂质过氧化抑制剂小分子安全有效地抑制脂质双层的过氧化，将大大推进许多流行的人类疾病的治疗，包括动脉粥样硬化、癌症、黄斑变性和关节炎。然而，已知的大多数O抗脂过氧化药物都有重要的局限性。例如，典型的类胡萝卜素，如O虾青素，具有很强的自我-羟基胡萝卜素倾向(1)-···典型的类胡萝卜素如O虾青素相比之下，有几个最近发现的Me Me OH“非典型”胡萝卜素具有潜在的Me通过Me O联黄素(2)自我保护的作用机制而具有特殊的抗脂过氧化活性。具体地说，该研究计划将开发高效灵活地合成HoO-Me非典型胡萝卜素Peridinin(1)、Ho-Me聚黄素(2)和二-[(6-O-油酰基-2-D-Ho-Me葡萄糖基)氧基]-虾青素(3)，对我进行系统的结构/功能研究，了解它们独特的抗脂过氧化OH谱，并通过合理指导的组合合成和di-[(6-O-oleoyl-！-D-glucopyranosyl)oxy]-astaxanthin(3)高通量筛选的迭代循环，广泛优化其Me-O-OH活性。PHS 398/2590(05/01版)页面续格式页面 公共卫生相关性：非典型类胡萝卜素的合成：脂质过氧化的自我保护抑制剂最近发现的几种天然产品具有在细胞膜内作为强大抗氧化剂的潜力，因此可能导致改进对各种流行疾病的治疗，包括动脉粥样硬化、癌症和关节炎。与之前研究过的相关抗氧化剂不同，这些新化合物不会自毁，因为它们保护细胞膜免受氧化损伤，这对最大化疗效和安全性至关重要。这项研究计划将导致高效的合成，详细的研究和广泛的优化这些新型的“自我保护”的抗氧化剂。PHS 398/2590(05/01版)页面续格式页面