title: Bivalent ligands incorporating curcumin and diosgenin as multifunctional compounds against Alzheimer's disease.
abstract: In an effort to combat the multifaceted nature of Alzheimer's disease (AD) progression, a series of multifunctional, bivalent compounds containing curcumin and diosgenin were designed, synthesized, and biologically characterized. Screening results in MC65 neuroblastoma cells established that compound 38 with a spacer length of 17 atoms exhibited the highest protective potency with an EC50 of 111.7 ± 9.0 nM. A reduction in protective activity was observed as spacer length was increased up to 28 atoms and there is a clear structural preference for attachment to the methylene carbon between the two carbonyl moieties of curcumin. Further study suggested that antioxidative ability and inhibitory effects on amyloid-β oligomer (AβO) formation may contribute to the neuroprotective outcomes. Additionally, compound 38 was found to bind directly to Aβ, similar to curcumin, but did not form complexes with the common biometals Cu, Fe, and Zn. Altogether, these results give strong evidence to support the bivalent design strategy in developing novel compounds with multifunctional ability for the treatment of AD.
authors.affiliation: School of Pharmacy-Department of Medicinal Chemistry, Virginia Commonwealth University, Biotech I, Suite 205, 800 E. Leigh St., PO Box 980540, Richmond, VA 23298, USA.
authors.forename: Jeremy E
authors.initials: JE
authors.lastname: Chojnacki
authors.affiliation: School of Pharmacy-Department of Medicinal Chemistry, Virginia Commonwealth University, Biotech I, Suite 205, 800 E. Leigh St., PO Box 980540, Richmond, VA 23298, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Liu
authors.affiliation: School of Pharmacy-Department of Medicinal Chemistry, Virginia Commonwealth University, Biotech I, Suite 205, 800 E. Leigh St., PO Box 980540, Richmond, VA 23298, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Saathoff
authors.affiliation: School of Pharmacy-Department of Medicinal Chemistry, Virginia Commonwealth University, Biotech I, Suite 205, 800 E. Leigh St., PO Box 980540, Richmond, VA 23298, USA. Electronic address: szhang2@vcu.edu.
authors.forename: Shijun
authors.initials: S
authors.lastname: Zhang
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism; D052160:Benzothiazoles; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003474:Curcumin / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D004144:Diosgenin / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D015195:Drug Design; D006801:Humans; D008024:Ligands; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D017382:Reactive Oxygen Species / Q000378:metabolism; D013844:Thiazoles / Q000737:chemistry / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D008024:Ligands; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D013844:Thiazoles; C009462:thioflavin T; D003474:Curcumin; D004144:Diosgenin
keywords: Alzheimer’s disease; Bivalent strategy; Caprospinol; Curcumin; Diosgenin; Natural products