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

非典型类胡萝卜素的合成：脂质过氧化的自我保护抑制剂安全有效地抑制脂质双分子层过氧化的小分子可以大大促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，大多数已知的O型抗脂质过氧化剂具有重要的局限性。 例如，典型的类胡萝卜素如O虾青素具有强烈的自我- Me HO Me多甲藻黄素的倾向（1）Me与活性氧Me物种的破坏性相互作用，这限制了脂质O保护作用的寿命，并导致产生HO Me Me有害的类胡萝卜素分解产物.相比之下，最近发现了几种Me Me Me Me OH“非典型”类胡萝卜素，它们具有通过Me O synechoxanthin（2）自我保护作用机制的特殊抗脂质过氧化活性的潜力。 具体地说，该研究计划将开发HO O O O Me非典型类胡萝卜素多甲素（1）、HO O Me聚胞黄质（2）和二-[（6-O-油酰基-2-D-HO Me Me Me Me吡喃葡萄糖基）氧基]-虾青素（3），对Me Me Me Me进行系统的结构/功能研究，以了解其独特的抗脂质过氧化剂OH谱，并通过理性指导的组合合成和高-二-[（6-O-油酰基-！D-吡喃葡萄糖基）氧基]-虾青素（3）通量筛选。PHS 398/2590（Rev. 05/01） 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物有可能在细胞膜内充当强大的抗氧化剂，因此可能导致各种流行疾病的治疗方法得到改善，包括动脉粥样硬化，癌症和关节炎。与之前研究的相关抗氧化剂相比，这些新化合物不会自我破坏，因为它们可以保护膜免受氧化损伤，这对于最大限度地提高功效和安全性至关重要。这项研究计划将导致这些新的“自我保护”抗氧化剂的有效合成，详细的研究和广泛的优化。PHS 398/2590（Rev. 05/01）

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