title: Design, Synthesis, and Characterization of 3-(Benzylidene)indolin-2-one Derivatives as Ligands for α-Synuclein Fibrils.
abstract: A series of 3-(benzylidine)indolin-2-one derivatives were synthesized and evaluated for their in vitro binding to alpha synuclein (α-syn), beta amyloid (Aβ), and tau fibrils. Compounds with a single double bond in the 3-position had only a modest affinity for α-syn and no selectivity for α-syn versus Aβ or tau fibrils. Homologation to the corresponding diene analogues yielded a mixture of Z,E and E,E isomers; substitution of the indoline nitrogen with an N-benzyl group resulted in increased binding to α-syn and reasonable selectivity for α-syn versus Aβ and tau. Introduction of a para-nitro group into the benzene ring of the diene enabled separation of the Z,E and E,E isomers and led to the identification of the Z,E configuration as the more active regioisomer. The data described here provide key structural information in the design of probes which bind preferentially to α-syn versus Aβ or tau fibrils.
authors.affiliation: †Department of Radiology, Washington University School of Medicine, St. Louis, Missouri 63110, United States.
authors.forename: Wenhua
authors.initials: W
authors.lastname: Chu
authors.affiliation: †Department of Radiology, Washington University School of Medicine, St. Louis, Missouri 63110, United States.
authors.forename: Dong
authors.initials: D
authors.lastname: Zhou
authors.affiliation: ‡Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, United States.
authors.forename: Vrinda
authors.initials: V
authors.lastname: Gaba
authors.affiliation: ‡Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, United States.
authors.forename: Jialu
authors.initials: J
authors.lastname: Liu
authors.affiliation: †Department of Radiology, Washington University School of Medicine, St. Louis, Missouri 63110, United States.
authors.forename: Shihong
authors.initials: S
authors.lastname: Li
authors.affiliation: †Department of Radiology, Washington University School of Medicine, St. Louis, Missouri 63110, United States.
authors.forename: Xin
authors.initials: X
authors.lastname: Peng
authors.affiliation: †Department of Radiology, Washington University School of Medicine, St. Louis, Missouri 63110, United States.
authors.forename: Jinbin
authors.initials: J
authors.lastname: Xu
authors.affiliation: ‡Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, United States.
authors.forename: Dhruva
authors.initials: D
authors.lastname: Dhavale
authors.affiliation: ‡Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, United States.
authors.forename: Devika P
authors.initials: DP
authors.lastname: Bagchi
authors.affiliation: §Department of Chemistry, Washington University, St. Louis, Missouri 63130, United States.
authors.forename: André
authors.initials: A
authors.lastname: d'Avignon
authors.affiliation: ∥MassGeneral Institute of Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, Massachusetts 02129, United States.
authors.forename: Naomi B
authors.initials: NB
authors.lastname: Shakerdge
authors.affiliation: ∥MassGeneral Institute of Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, Massachusetts 02129, United States.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Bacskai
authors.affiliation: †Department of Radiology, Washington University School of Medicine, St. Louis, Missouri 63110, United States.
authors.forename: Zhude
authors.initials: Z
authors.lastname: Tu
authors.affiliation: ‡Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, United States.
authors.forename: Paul T
authors.initials: PT
authors.lastname: Kotzbauer
authors.affiliation: †Department of Radiology, Washington University School of Medicine, St. Louis, Missouri 63110, United States.|∥MassGeneral Institute of Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, Massachusetts 02129, United States.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Mach
mesh_terms: D015195:Drug Design; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry*; D008024:Ligands; D008856:Microscopy, Fluorescence; D051844:alpha-Synuclein / Q000737:chemistry*
chemical_list: D007211:Indoles; D008024:Ligands; D051844:alpha-Synuclein