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

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Synthetic and Biological Chemistry A Study Section (SBCA)
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Fabian, Miles
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University of Illinois Urbana-Champaign
Schools of Arts and Sciences
United States
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Woerly, Eric M; Roy, Jahnabi; Burke, Martin D (2014) Synthesis of most polyene natural product motifs using just 12 building blocks and one coupling reaction. Nat Chem 6:484-91
Fujii, Seiko; Chang, Stephanie Y; Burke, Martin D (2011) Total synthesis of synechoxanthin through iterative cross-coupling. Angew Chem Int Ed Engl 50:7862-4
Woerly, Eric M; Cherney, Alan H; Davis, Erin K et al. (2010) Stereoretentive Suzuki-Miyaura coupling of haloallenes enables fully stereocontrolled access to (-)-peridinin. J Am Chem Soc 132:6941-3