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J Med Chem. 2015 Aug 13;58(15):6002-17. doi: 10.1021/acs.jmedchem.5b00571. Epub 2015 Jul 31.

Design, Synthesis, and Characterization of 3-(Benzylidene)indolin-2-one Derivatives as Ligands for α-Synuclein Fibrils.

Author information

1
†Department of Radiology, Washington University School of Medicine, St. Louis, Missouri 63110, United States.
2
‡Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, United States.
3
§Department of Chemistry, Washington University, St. Louis, Missouri 63130, United States.
4
∥MassGeneral Institute of Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, Massachusetts 02129, United States.

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.

PMID:
26177091
PMCID:
PMC4624220
DOI:
10.1021/acs.jmedchem.5b00571
[Indexed for MEDLINE]
Free PMC Article

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