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

作者：Chu Wenhua; Zhou Dong; Gaba Vrinda; Liu Jialu; Li Shihong; Peng Xin; Xu Jinbin; Dhavale Dhruva; Bagchi Devika P; d'Avignon Andre; Shakerdge Naomi B; Bacskai Brian J; Tu Zhude; Kotzbauer Paul T; Mach Robert H^*

来源：Journal of Medicinal Chemistry, 2015, 58(15): 6002-6017.

DOI：10.1021/acs.jmedchem.5b00571

A series of 3-(benzylidine)indolin-2-one derivatives were synthesized and evaluated for their in vitro binding to alpha synuclein (alpha-syn), beta amyloid (A beta), and tau fibrils. Compounds with a single double bond in the 3-position had only a modest affinity for alpha-syn and no selectivity for alpha-syn versus A beta 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 alpha-syn and reasonable selectivity for alpha-syn versus 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 alpha-syn versus A beta or tau fibrils.

• 出版日期2015-8-13