Document Detail


Diaryl hydrazones as multifunctional inhibitors of amyloid self-assembly.
MedLine Citation:
PMID:  23346953     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The design and application of an effective, new class of multifunctional small molecule inhibitors of amyloid self-assembly are described. Several compounds based on the diaryl hydrazone scaffold were designed. Forty-four substituted derivatives of this core structure were synthesized using a variety of benzaldehydes and phenylhydrazines and characterized. The inhibitor candidates were evaluated in multiple assays, including the inhibition of amyloid β (Aβ) fibrillogenesis and oligomer formation and the reverse processes, the disassembly of preformed fibrils and oligomers. Because the structure of the hydrazone-based inhibitors mimics the redox features of the antioxidant resveratrol, the radical scavenging effect of the compounds was evaluated by colorimetric assays against 2,2-diphenyl-1-picrylhydrazyl and superoxide radicals. The hydrazone scaffold was active in all of the different assays. The structure-activity relationship revealed that the substituents on the aromatic rings had a considerable effect on the overall activity of the compounds. The inhibitors showed strong activity in fibrillogenesis inhibition and disassembly, and even greater potency in the inhibition of oligomer formation and oligomer disassembly. Supporting the quantitative fluorometric and colorimetric assays, size exclusion chromatographic studies indicated that the best compounds practically eliminated or substantially inhibited the formation of soluble, aggregated Aβ species, as well. Atomic force microscopy was also applied to monitor the morphology of Aβ deposits. The compounds also possessed the predicted antioxidant properties; approximately 30% of the synthesized compounds showed a radical scavenging effect equal to or better than that of resveratrol or ascorbic acid.
Authors:
Béla Török; Abha Sood; Seema Bag; Rekha Tulsan; Sanjukta Ghosh; Dmitry Borkin; Arleen R Kennedy; Michelle Melanson; Richard Madden; Weihong Zhou; Harry Levine; Marianna Török
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-02-06
Journal Detail:
Title:  Biochemistry     Volume:  52     ISSN:  1520-4995     ISO Abbreviation:  Biochemistry     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-02-19     Completed Date:  2013-04-26     Revised Date:  2014-02-20    
Medline Journal Info:
Nlm Unique ID:  0370623     Medline TA:  Biochemistry     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1137-48     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Amyloid / antagonists & inhibitors*
Amyloid beta-Peptides / antagonists & inhibitors,  chemistry,  metabolism
Antioxidants / chemistry,  pharmacology*
Biphenyl Compounds / chemistry
Drug Design
Drug Evaluation, Preclinical / methods
Hydrazones / chemical synthesis,  chemistry*,  pharmacology*
Microscopy, Atomic Force
Molecular Structure
Picrates / chemistry
Structure-Activity Relationship*
Superoxides / chemistry
Grant Support
ID/Acronym/Agency:
R-15 AG025777-03A1/AG/NIA NIH HHS; R15 AG025777/AG/NIA NIH HHS; R21 AG028816/AG/NIA NIH HHS; R21AG028816-01/AG/NIA NIH HHS
Chemical
Reg. No./Substance:
0/Amyloid; 0/Amyloid beta-Peptides; 0/Antioxidants; 0/Biphenyl Compounds; 0/Hydrazones; 0/Picrates; 11062-77-4/Superoxides; 1898-66-4/2,2-diphenyl-1-picrylhydrazyl
Comments/Corrections

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