Biflavonoids are superior to monoflavonoids in inhibiting amyloid-β toxicity and fibrillogenesis via accumulation of nontoxic oligomer-like structures.
ABSTRACT Polymerization of monomeric amyloid-β peptides (Aβ) into soluble oligomers and insoluble fibrils is one of the major pathways triggering the pathogenesis of Alzheimer's disease (AD). Using small molecules to prevent the polymerization of Aβ peptides can, therefore, be an effective therapeutic strategy for AD. In this study, we investigate the effects of mono- and biflavonoids in Aβ42-induced toxicity and fibrillogenesis and find that the biflavonoid taiwaniaflavone (TF) effectively and specifically inhibits Aβ toxicity and fibrillogenesis. Compared to TF, the monoflavonoid apigenin (AP) is less effective and less specific. Our data show that differential effects of the mono- and biflavonoids in Aβ fibrillogenesis correlate with their varying cytoprotective efficacies. We also find that other biflavonoids, namely, 2',8''-biapigenin, amentoflavone, and sumaflavone, can also effectively inhibit Aβ toxicity and fibrillogenesis, implying that the participation of two monoflavonoids in a single biflavonoid molecule enhances their activity. Biflavonoids, while strongly inhibiting Aβ fibrillogenesis, accumulate nontoxic Aβ oligomeric structures, suggesting that these are off-pathway oligomers. Moreover, TF abrogates the toxicity of preformed Aβ oligomers and fibrils, indicating that TF and other biflavonoids may also reduce the toxicity of toxic Aβ species. Altogether, our data clearly show that biflavonoids, possibly because of the possession of two Aβ binders separated by an appropriate size linker, are likely to be promising therapeutics for suppressing Aβ toxicity.
Article: Total synthesis of ochnaflavone.[show abstract] [hide abstract]
ABSTRACT: The first total syntheses of ochnaflavone, an asymmetric biflavone consisting of apigenin and luteolin moieties, and the permethyl ether of 2,3,2'',3''-tetrahydroochnaflavone have been achieved. The key steps in the synthesis of ochnaflavone were the formation of a diaryl ether and ring cyclization of an ether-linked dimeric chalcone to assemble the two flavone nuclei. Optimal experimental conditions for the oxidative cyclization to form ochnaflavone were established.Beilstein Journal of Organic Chemistry 01/2013; 9:1346-51. · 2.80 Impact Factor
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ABSTRACT: Halogenation of organic compounds plays diverse roles in biochemistry, including selective chemical modification of proteins and improved oral absorption/blood-brain barrier permeability of drug candidates. Moreover, halogenation of aromatic molecules greatly affects aromatic interaction-mediated self-assembly processes, including amyloid fibril formation. Perturbation of the aromatic interaction caused by halogenation of peptide building blocks is known to affect the morphology and other physical properties of the fibrillar structure. Consequently, in this article, we investigated the ability of halogenated ligands to modulate the self-assembly of amyloidogenic peptide/protein. As a model system, we chose amyloid-beta peptide (Aβ), which is implicated in Alzheimer's disease, and a novel modulator of Aβ aggregation, erythrosine B (ERB). Considering that four halogen atoms are attached to the xanthene benzoate group in ERB, we hypothesized that halogenation of the xanthene benzoate plays a critical role in modulating Aβ aggregation and cytotoxicity. Therefore, we evaluated the modulating capacities of four ERB analogs containing different types and numbers of halogen atoms as well as fluorescein as a negative control. We found that fluorescein is not an effective modulator of Aβ aggregation and cytotoxicity. However, halogenation of either the xanthenes or benzoate ring of fluorescein substantially enhanced the inhibitory capacity on Aβ aggregation. Such Aβ aggregation inhibition by ERB analogs except rose bengal correlated well to the inhibition of Aβ cytotoxicity. To our knowledge, this is the first report demonstrating that halogenation of aromatic rings substantially enhance inhibitory capacities of small molecules on Aβ-associated neurotoxicity via Aβ aggregation modulation.PLoS ONE 01/2013; 8(2):e57288. · 3.73 Impact Factor
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ABSTRACT: Early plants began colonizing the terrestrial earth approximately 450 million years ago. Their success on land has been partially attributed to the evolution of specialized metabolic systems from core metabolic pathways, the former yielding structurally and functionally diverse chemicals to cope with a myriad of biotic and abiotic ecological pressures. Over the past two decades, functional genomics, primarily focused on flowering plants, has begun cataloging the biosynthetic players underpinning assorted classes of plant specialized metabolites. However, the molecular mechanisms enriching specialized metabolic pathways during land plant evolution remain largely unexplored. Selaginella is an extant lycopodiophyte genus representative of an ancient lineage of tracheophytes. Notably, the lycopodiophytes diverged from euphyllophytes over 400 million years ago. The recent completion of the whole-genome sequence of an extant lycopodiophyte, S. moellendorffii, provides new genomic and biochemical resources for studying metabolic evolution in vascular plants. 400 million years of independent evolution of lycopodiophytes and euphyllophytes resulted in numerous metabolic traits confined to each lineage. Surprisingly, a cadre of specialized metabolites, generally accepted to be restricted to seed plants, have been identified in Selaginella. Initial work suggested that Selaginella lacks obvious catalytic homologs known to be involved in the biosynthesis of well-studied specialized metabolites in seed plants. Therefore, these initial functional analyses suggest that the same chemical phenotypes arose independently more commonly than anticipated from our conventional understanding of the evolution of metabolism. Notably, the emergence of analogous and homologous catalytic machineries through convergent and parallel evolution, respectively, seems to have occurred repeatedly in different plant lineages.Frontiers in Plant Science 01/2013; 4:119.