title: "Clicked" bivalent ligands containing curcumin and cholesterol as multifunctional abeta oligomerization inhibitors: design, synthesis, and biological characterization.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Lenhart
authors.forename: Xiao
authors.initials: X
authors.lastname: Ling
authors.forename: Ronak
authors.initials: R
authors.lastname: Gandhi
authors.forename: Tai L
authors.initials: TL
authors.lastname: Guo
authors.forename: Phillip M
authors.initials: PM
authors.lastname: Gerk
authors.forename: Darlene H
authors.initials: DH
authors.lastname: Brunzell
authors.forename: Shijun
authors.initials: S
authors.lastname: Zhang
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000975:Antioxidants / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D002784:Cholesterol / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D003474:Curcumin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D021962:Membrane Microdomains / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D055503:Protein Multimerization; D013329:Structure-Activity Relationship
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D016229:Amyloid beta-Peptides; D000975:Antioxidants; D008024:Ligands; D002784:Cholesterol; D003474:Curcumin