Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Synthesis of tetrahydroxybiphenyls and tetrahydroxyterphenyls and their evaluation as amyloid-? aggregation inhibitors.

ABSTRACT: 3,3',4,4'-Tetrahydroxybiphenyl and three isomeric 3,3?,4,4?-tetrahydroxyterphenyls with varying geometries around the central phenyl ring have been synthesized and evaluated for their in vitro activity against aggregation of Alzheimer's amyloid-? peptide (A?). Results from Congo red spectral-shift assays reveal that all four compounds successfully inhibit association of A? monomers. For the tetrahydroxyterphenyls, efficacy varies with linker geometry: the ortho-arrangement affords the most successful inhibition and the para-geometry the least, perhaps due to differing abilities of these compounds to bind A?. Of the four small molecules studied, 3,3',4,4'-tetrahydroxybiphenyl is the most effective inhibitor, reducing A? aggregation by 50% when present in stoichiometric concentrations.

SUBMITTER: Stevens CB

PROVIDER: S-EPMC3594554 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Synthesis of tetrahydroxybiphenyls and tetrahydroxyterphenyls and their evaluation as amyloid-β aggregation inhibitors.

Stevens Craig B CB Hanna James M JM Lammi Robin K RK

Bioorganic & medicinal chemistry letters 20130204 6

3,3',4,4'-Tetrahydroxybiphenyl and three isomeric 3,3″,4,4″-tetrahydroxyterphenyls with varying geometries around the central phenyl ring have been synthesized and evaluated for their in vitro activity against aggregation of Alzheimer's amyloid-β peptide (Aβ). Results from Congo red spectral-shift assays reveal that all four compounds successfully inhibit association of Aβ monomers. For the tetrahydroxyterphenyls, efficacy varies with linker geometry: the ortho-arrangement affords the most succe ...[more]

PMID: 23403086

Similar Datasets

Multicomponent Synthesis of Polyphenols and their in vitro Evaluation as Potential β-Amyloid Aggregation Inhibitors.

Project description:While plant polyphenols possess a variety of biological properties, exploration of chemical diversity around them is still problematic. Here, an example of application of the Ugi multicomponent reaction to the combinatorial assembly of artificial, yet "natural-like", polyphenols is presented. The synthesized compounds represent a second-generation library directed to the inhibition of β-amyloid protein aggregation. Chiral enantiopure compounds, and polyphenol-β-lactam hybrids have been prepared too. The biochemical assays have highlighted the importance of the key pharmacophores in these compounds. A lead for inhibition of aggregation of truncated protein AβpE3-42 was selected.

| S-EPMC6680962 | biostudies-literature

Synthesis and Biological Assessment of 2-Hydroxyiminoethanones as Anti-Inflammatory and β-Amyloid Aggregation Inhibitors.

Project description:Alzheimer's disease (AD) is a neuroinflammatory based pathologic state in which β-amyloid aggregates are major devastating agents. In this study, a series of 2-hydroxyiminoethanones were synthesized and evaluated as anti-inflammatory in carrageenan and formalin tests and inhibitors of β-amyloid aggregation. Compounds 1-10b were synthesized through a two-step reaction. Results: Compounds 1-5b showed more β-amyloid disaggregation ability than reference drugs rifampicin and donepezil and compound 2b was the best compound in this series and could reduce the extent of amyloid aggregation to 50.9%. Interestingly, compounds 1b and 3b showed significant anti-inflammatory activity in carrageenan-induced paw edema compared to control group and equivalent to the reference drug indomethacin. 2-Hydeoxyiminoethanones are privileged scaffold for further drug research and development as anti-neuroinflammatory and neuroprotective agents.

| S-EPMC6934981 | biostudies-literature

Acetylcholinesterase inhibitors with photoswitchable inhibition of ?-amyloid aggregation.

Project description:Photochromic cholinesterase inhibitors were obtained from cis-1,2-?-dithienylethene-based compounds by incorporating one or two aminopolymethylene tacrine groups. All target compounds are potent acetyl- (AChE) and butyrylcholinesterase (BChE) inhibitors in the nanomolar concentration range. Compound 11b bearing an octylene linker exhibited interactions with both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Yet upon irradiation with light, the mechanism of interaction varied from one photochromic form to another, which was investigated by kinetic studies and proved "photoswitchable". The AChE-induced ?-amyloid (A?) aggregation assay gave further experimental support to this finding: A?1-40 aggregation catalyzed by the PAS of AChE might be inhibited by compound 11b in a concentration-dependent manner and seems to occur only with one photochromic form. Computational docking studies provided potential binding modes of the compound. Docking studies and molecular dynamics (MD) simulations for the ring-open and -closed form indicate a difference in binding. Although both forms can interact with the PAS, more stable interactions are observed for the ring-open form based upon stabilization of a water molecule network within the enzyme, whereas the ring-closed form lacks the required conformational flexibility for an analogous binding mode. The photoswitchable inhibitor identified might serve as valuable molecular tool to investigate the different biological properties of AChE as well as its role in pathogenesis of AD in in vitro assays.

| S-EPMC4030803 | biostudies-literature

Thermodynamic and kinetic design principles for amyloid-aggregation inhibitors.

Project description:Understanding the mechanism of action of compounds capable of inhibiting amyloid-fibril formation is critical to the development of potential therapeutics against protein-misfolding diseases. A fundamental challenge for progress is the range of possible target species and the disparate timescales involved, since the aggregating proteins are simultaneously the reactants, products, intermediates, and catalysts of the reaction. It is a complex problem, therefore, to choose the states of the aggregating proteins that should be bound by the compounds to achieve the most potent inhibition. We present here a comprehensive kinetic theory of amyloid-aggregation inhibition that reveals the fundamental thermodynamic and kinetic signatures characterizing effective inhibitors by identifying quantitative relationships between the aggregation and binding rate constants. These results provide general physical laws to guide the design and optimization of inhibitors of amyloid-fibril formation, revealing in particular the important role of on-rates in the binding of the inhibitors.

| S-EPMC7533883 | biostudies-literature

Design of ?-amyloid aggregation inhibitors from a predicted structural motif.

Project description:Drug design studies targeting one of the primary toxic agents in Alzheimer's disease, soluble oligomers of amyloid ?-protein (A?), have been complicated by the rapid, heterogeneous aggregation of A? and the resulting difficulty to structurally characterize the peptide. To address this, we have developed [Nle(35), D-Pro(37)]A?(42), a substituted peptide inspired from molecular dynamics simulations which forms structures stable enough to be analyzed by NMR. We report herein that [Nle(35), D-Pro(37)]A?(42) stabilizes the trimer and prevents mature fibril and ?-sheet formation. Further, [Nle(35), D-Pro(37)]A?(42) interacts with WT A?(42) and reduces aggregation levels and fibril formation in mixtures. Using ligand-based drug design based on [Nle(35), D-Pro(37)]A?(42), a lead compound was identified with effects on inhibition similar to the peptide. The ability of [Nle(35), D-Pro(37)]A?(42) and the compound to inhibit the aggregation of A?(42) provides a novel tool to study the structure of A? oligomers. More broadly, our data demonstrate how molecular dynamics simulation can guide experiment for further research into AD.

| S-EPMC3766731 | biostudies-literature

Novel curcumin derivatives as potent inhibitors of amyloid β aggregation.

Project description:Modulation of abnormal amyloid β (Aβ) aggregation is considered to be a potential therapeutic target for Alzheimer's disease (AD). Recent in vitro and in vivo experiments suggest that inhibition of Aβ aggregation by curcumin would exert favorable effects for preventing or treating AD. We have previously synthesized a series of novel curcumin derivatives. In this study, we investigated the effects of our curcumin derivatives on Aβ aggregation and the cell toxicities of Aβ aggregates. According to sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) profiles, 14 of 41 compounds showed a significant increase in the densities of the bands of Aβ (1-42) by incubation during the aggregation process relative to those of Aβ (1-42) prepared in the presence of the vehicle control. Of the 14 compounds, four compounds additionally reduced cell toxicity of the Aβ aggregates by incubation during the aggregation process. A significant positive correlation was observed between the cell viability and densities of the bands at ranges of 15-20, 20-37, 37-75, and 75-200 kDa in SDS-PAGE. On the basis of these results, we propose four curcumin derivatives with potential for preventing AD. These curcumin derivatives exhibited high inhibitory effects on Aβ aggregation and induced the formation of lower molecular size Aβ species that have weaker cell toxicity. These compounds may exert therapeutic effects on AD in future in vivo studies.

| S-EPMC5669405 | biostudies-literature

d-Amino Acid Pseudopeptides as Potential Amyloid-Beta Aggregation Inhibitors.

Project description:A causative factor for neurotoxicity associated with Alzheimer's disease is the aggregation of the amyloid-β (Aβ) peptide into soluble oligomers. Two all d-amino acid pseudo-peptides, SGB1 and SGD1, were designed to stop the aggregation. Molecular dynamics (MD) simulations have been carried out to study the interaction of the pseudo-peptides with both Aβ13⁻23 (the core recognition site of Aβ) and full-length Aβ1⁻42. Umbrella sampling MD calculations have been used to estimate the free energy of binding, ∆G, of these peptides to Aβ13⁻23. The highest ∆Gbinding is found for SGB1. Each of the pseudo-peptides was also docked to Aβ1⁻42 and subjected up to seven microseconds of all atom molecular dynamics simulations. The resulting structures lend insight into how the dynamics of Aβ1⁻42 are altered by complexation with the pseudo-peptides and confirmed that SGB1 may be a better candidate for developing into a drug to prevent Alzheimer's disease.

| S-EPMC6225248 | biostudies-literature

Novel transthyretin amyloid fibril formation inhibitors: synthesis, biological evaluation, and X-ray structural analysis.

Project description:Transthyretin (TTR) is one of thirty non-homologous proteins whose misfolding, dissociation, aggregation, and deposition is linked to human amyloid diseases. Previous studies have identified that TTR amyloidogenesis can be inhibited through stabilization of the native tetramer state by small molecule binding to the thyroid hormone sites of TTR. We have evaluated a new series of beta-aminoxypropionic acids (compounds 5-21), with a single aromatic moiety (aryl or fluorenyl) linked through a flexible oxime tether to a carboxylic acid. These compounds are structurally distinct from the native ligand thyroxine and typical halogenated biaryl NSAID-like inhibitors to avoid off-target hormonal or anti-inflammatory activity. Based on an in vitro fibril formation assay, five of these compounds showed significant inhibition of TTR amyloidogenesis, with two fluorenyl compounds displaying inhibitor efficacy comparable to the well-known TTR inhibitor diflunisal. Fluorenyl 15 is the most potent compound in this series and importantly does not show off-target anti-inflammatory activity. Crystal structures of the TTR:inhibitor complexes, in agreement with molecular docking studies, revealed that the aromatic moiety, linked to the sp(2)-hybridized oxime carbon, specifically directed the ligand in either a forward or reverse binding mode. Compared to the aryl family members, the bulkier fluorenyl analogs achieved more extensive interactions with the binding pockets of TTR and demonstrated better inhibitory activity in the fibril formation assay. Preliminary optimization efforts are described that focused on replacement of the C-terminal acid in both the aryl and fluorenyl series (compounds 22-32). The compounds presented here constitute a new class of TTR inhibitors that may hold promise in treating amyloid diseases associated with TTR misfolding.

| S-EPMC2709434 | biostudies-literature

A?42-binding peptoids as amyloid aggregation inhibitors and detection ligands.

Project description:Alzheimer's disease (AD) is the most common form of dementia and currently affects 5.4 million Americans. A number of anti-A? (beta amyloid) therapeutic agents have been developed for AD, but so far all of them failed in clinic. Here we used peptoid chemistry to develop ligands selective for A?42. Peptoids are N-substituted glycine oligomers, a class of peptidomimics. We synthesized an on-bead peptoid library consisting of 38,416 unique peptoids. The generated peptoid library was screened and arrays of A?42-selective peptoid ligands were identified. One of those peptoid ligands, IAM1 (inhibitor of amyloid), and the dimeric form (IAM1)2 were synthesized and evaluated in a variety of biochemical assays. We discovered that IAM1 selectively binds to A?42, while the dimeric derivative (IAM1)2 has a higher affinity for A?42. Furthermore, we demonstrated that IAM1 and (IAM1)2 were able to inhibit the aggregation of A?42 in a concentration-dependent manner, and that (IAM1)2 protected primary hippocampal neurons from the A?-induced toxicity in vitro. These results suggest that IAM1 and (IAM1)2 are specific A?42 ligands with antiaggregation and neuroprotective properties. IAM1, (IAM1)2, and their derivatives hold promise as A?42 detection agents and as lead compounds for the development of AD therapeutic agents.

| S-EPMC3689191 | biostudies-literature

Disease-modifying anti-Alzheimer's drugs: inhibitors of human cholinesterases interfering with ?-amyloid aggregation.

Project description:AIMS:We recently described multifunctional tools (2a-c) as potent inhibitors of human Cholinesterases (ChEs) also able to modulate events correlated with A? aggregation. We herein propose a thorough biological and computational analysis aiming at understanding their mechanism of action at the molecular level. METHODS:We determined the inhibitory potency of 2a-c on A?1-42 self-aggregation, the interference of 2a with the toxic A? oligomeric species and with the postaggregation states by capillary electrophoresis analysis and transmission electron microscopy. The modulation of A? toxicity was assessed for 2a and 2b on human neuroblastoma cells. The key interactions of 2a with A? and with the A?-preformed fibrils were computationally analyzed. 2a-c toxicity profile was also assessed (human hepatocytes and mouse fibroblasts). RESULTS:Our prototypical pluripotent analogue 2a interferes with A? oligomerization process thus reducing A? oligomers-mediated toxicity in human neuroblastoma cells. 2a also disrupts preformed fibrils. Computational studies highlighted the bases governing the diversified activities of 2a. CONCLUSION:Converging analytical, biological, and in silico data explained the mechanism of action of 2a on A?1-42 oligomers formation and against A?-preformed fibrils. This evidence, combined with toxicity data, will orient the future design of safer analogues.

| S-EPMC6493034 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data