title: Total Synthesis Confirms the Molecular Structure Proposed for Oxidized Levuglandin D2.
abstract: Levuglandins (LG)D2and LGE2are γ-ketoaldehyde levulinaldehyde derivatives with prostanoid side chains produced by spontaneous rearrangement of the endoperoxide intermediate PGH2in the biosynthesis of prostaglandins. Covalent adduction of LGs with the amyloid peptide Aβ1-42promotes formation of the type of oligomers that have been associated with neurotoxicity and are a pathologic hallmark of Alzheimer's disease. Within 1 min of their generation during the production of PGH2by cyclooxygenation of arachidonic acid, LGs are sequestered by covalent adduction to proteins. In view of this high proclivity for covalent adduction, it is understandable that free LGs have never been detected in vivo. Recently a catabolite, believed to be an oxidized derivative of LGD2(ox-LGD2), a levulinic acid hydroxylactone with prostanoid side chains, was isolated from the red alga Gracilaria edulis and detected in mouse tissues and in the lysate of phorbol-12-myristate-13-acetate-treated THP-1 cells incubated with arachidonic acid. Such oxidative catabolism of LGD2is remarkable because it must be outstandingly efficient to prevail over adduction with proteins and because it requires a unique dehydrogenation. We now report a concise total synthesis that confirms the molecular structure proposed for ox-LGD2. The synthesis also produces ox-LGE2, which readily undergoes allylic rearrangement to Δ6-ox-LGE2.
authors.affiliation: Department of Chemistry, Case Western Reserve University , Cleveland, Ohio 44106, United States.
authors.forename: Yu-Shiuan
authors.identifier: 0000-0002-7408-7888
authors.initials: YS
authors.lastname: Cheng
authors.affiliation: Department of Chemistry, Case Western Reserve University , Cleveland, Ohio 44106, United States.
authors.forename: Wenyuan
authors.initials: W
authors.lastname: Yu
authors.affiliation: Department of Chemistry, Case Western Reserve University , Cleveland, Ohio 44106, United States.
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Chemistry, Case Western Reserve University , Cleveland, Ohio 44106, United States.
authors.forename: Robert G
authors.identifier: 0000-0001-9456-3557
authors.initials: RG
authors.lastname: Salomon
mesh_terms: D000818:Animals; D044724:Gracilaria / Q000737:chemistry*; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D010084:Oxidation-Reduction; D010703:Phorbol Esters / Q000494:pharmacology; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D011506:Proteins / Q000378:metabolism
chemical_list: D010703:Phorbol Esters; D011506:Proteins; C570744:levuglandin D2; C119222:phorbol-12-myristate; D015230:Prostaglandin D2