Document Detail

"Clicked" bivalent ligands containing curcumin and cholesterol as multifunctional abeta oligomerization inhibitors: design, synthesis, and biological characterization.
MedLine Citation:
PMID:  20666513     Owner:  NLM     Status:  MEDLINE    
In our effort to develop multifunctional compounds that cotarget beta-amyloid oligomers (AbetaOs), cell membrane/lipid rafts (CM/LR), and oxidative stress, a series of bivalent multifunctional Abeta oligomerization inhibitors (BMAOIs) containing cholesterol and curcumin were designed, synthesized, and biologically characterized as potential treatments for Alzheimer's disease (AD). The in vitro assay results established that the length of spacer that links cholesterol and curcumin and the attaching position of the spacer on curcumin are important structural determinants for their biological activities. Among the BMAOIs tested, 14 with a 21-atom-spacer was identified to localize to the CM/LR of human neuroblastoma MC65 cells, to inhibit the formation of AbetaOs in MC65 cells, to protect cells from AbetaOs-induced cytotoxicity, and to retain antioxidant properties of curcumin. Furthermore, 14 was confirmed to have the potential to cross the blood-brain barrier (BBB) as demonstrated in a Caco-2 cell model. Collectively, these results strongly encourage further optimization of 14 as a new hit to develop more potent BMAOIs.
James A Lenhart; Xiao Ling; Ronak Gandhi; Tai L Guo; Phillip M Gerk; Darlene H Brunzell; Shijun Zhang
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  53     ISSN:  1520-4804     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2010 Aug 
Date Detail:
Created Date:  2010-08-19     Completed Date:  2010-09-16     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  6198-209     Citation Subset:  IM    
Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA 23298, USA.
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MeSH Terms
Amyloid beta-Protein / metabolism*
Antioxidants / chemical synthesis*,  pharmacology
Cell Line, Tumor
Cell Membrane Permeability
Cholesterol / analogs & derivatives*,  chemical synthesis*,  pharmacology
Curcumin / analogs & derivatives*,  chemical synthesis*,  pharmacology
Membrane Microdomains / metabolism
Oxidative Stress / drug effects
P-Glycoprotein / metabolism
Protein Multimerization
Structure-Activity Relationship
Reg. No./Substance:
0/Amyloid beta-Protein; 0/Antioxidants; 0/Ligands; 0/P-Glycoprotein; 458-37-7/Curcumin; 57-88-5/Cholesterol

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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