Design, Synthesis, and Characterization of 3-(Benzylidene)indolin-2-one Derivatives as Ligands for 伪-Synuclein Fibrils
详细信息 查看全文
- 作者：Wenhua Chu ; Dong Zhou ; Vrinda Gaba ; Jialu Liu ; Shihong Li ; Xin Peng ; Jinbin Xu ; Dhruva Dhavale ; Devika P. Bagchi ; Andr茅 d鈥橝vignon ; Naomi B. Shakerdge ; Brian J. Bacskai ; Zhude Tu ; Paul T. Kotzbauer ; Robert H. Mach
- 刊名：Journal of Medicinal Chemistry
- 出版年：2015
- 出版时间：August 13, 2015
- 年：2015
- 卷：58
- 期：15
- 页码：6002-6017
- 全文大小：649K
- ISSN：1520-4804
文摘
A series of 3-(benzylidine)indolin-2-one derivatives were synthesized and evaluated for their in vitro binding to alpha synuclein (伪-syn), beta amyloid (A尾), and tau fibrils. Compounds with a single double bond in the 3-position had only a modest affinity for 伪-syn and no selectivity for 伪-syn versus A尾 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 伪-syn and reasonable selectivity for 伪-syn versus A尾 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 伪-syn versus A尾 or tau fibrils.