Following the heme paradigm, it is often proposed that dioxygen activation by nonheme monoiron enzymes involves an iron(IV)=oxo intermediate that is responsible for the substrate oxidation step. Such a transient species has now been obtained from a synthetic complex with a nonheme macrocyclic ligand and characterized spectroscopically. Its high-resolution crystal structure reveals an iron-oxygen bond length of 1.646(3) angstroms, demonstrating that a terminal iron(IV)=oxo unit can exist in a nonporphyrin ligand environment and lending credence to proposed mechanisms of nonheme iron catalysis.
The accumulation of metal ions and amyloid-β (Aβ) aggregates found in the brain of patients with Alzheimer's disease (AD) has been suggested to be involved in AD pathogenesis. To investigate metal-Aβ-associated pathways in AD, development of chemical tools to target metal-Aβ species is desired. Only a few efforts, however, have been reported. Here, we report bifunctional small molecules, N-(pyridin-2-ylmethyl)aniline (L2-a) and N 1 ,N 1 -dimethyl-N 4 -(pyridin-2-ylmethyl)benzene-1,4-diamine (L2-b) that can interact with both metal ions and Aβ species, as determined by spectroscopic methods including high-resolution NMR spectroscopy. Using the bifunctional compound L2-b, metal-induced Aβ aggregation and neurotoxicity were modulated in vitro as well as in human neuroblastoma cells. Furthermore, treatment of human AD brain tissue homogenates containing metal ions and Aβ species with L2-b showed disassembly of Aβ aggregates. Therefore, our studies presented herein demonstrate the value of bifunctional compounds as chemical tools for investigating metal-Aβ-associated events and their mechanisms in the development and pathogenesis of AD and as potential therapeutics.amyloid-β peptide | copper | zinc | reactive oxygen species | rational structure-based design M ore than 24 million people worldwide have Alzheimer's disease (AD), a devastating and fatal form of dementia (1-3). The key pathological markers in AD are amyloid-β (Aβ) plaques and neurofibrillary tangles, the accumulation of which is accompanied by oxidative stress, inflammation, and neurodegeneration. The "amyloid hypothesis" in AD states that Aβ, generated via cleavage of the amyloid precursor protein (APP) by β-and γ-secretases, is a proximal causative agent (1-4). It is, however, still unclear which morphological Aβ species, from soluble small oligomers to large fibrils, are central to AD pathogenesis (1-5).In addition to Aβ aggregate deposits, dyshomeostasis and miscompartmentalization of metal ions such as Fe, Cu, and Zn ions clearly occur in AD brains (1-4, 6-10). Some studies suggest that highly concentrated metal ions play an important role in Aβ aggregate deposition and neurotoxicity including the formation of reactive oxygen species (ROS) such as hydrogen peroxide (H 2 O 2 ) (1-4, 6-13). The role of metal ions in AD and molecular mechanisms of metal-Aβ-associated pathological pathways, however, are not fully understood. Using traditional metal chelating agents, potential regulation of metal-induced Aβ aggregation and neurotoxicity has been shown in vitro and in vivo (1-4, 6, 10, 13-17). Some compounds such as clioquinol (CQ) and an 8-hydroxyquinoline derivative (PBT2) have moved into clinical trials and showed improved cognition. Long-term use of CQ is, however, limited by an adverse side effect, subacute myelo-optic neuropathy (18). Although these traditional metal chelators have yet to be available as therapeutic agents, the studies using these compounds show the possible involvement of metal ions in AD pathogenesis.To elucidate the pathological ...
high-valent iron-oxo ͉ oxygen activation ͉ oxygenases
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