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Hybrids of oxoisoaporphine–tetrahydroisoquinoline: novel multi-target inhibitors of inflammation and amyloid-β aggregation in Alzheimer’s disease

  • Yusi Chen
  • Chunlin Su
  • Li Wang
  • Jingfang Qin
  • Shenqi Wei
  • Huang TangEmail author
Original Article

Abstract

A series of 8- and 11-substituted hybrids of oxoisoaporphine–tetrahydroisoquinoline have been designed and synthesized. The new derivatives strongly suppressed NO and iNOS production and modulated the production of cytokines by decreasing TNF-α and IL-1β formation in lipopolysaccharide-activated BV-2 microglia and RAW 264.7 macrophages. Meanwhile, incubation of these derivatives with SH-SY5Y cells that were transfected with human APP containing the Swedish mutations significantly decreased the secretion of Aβ42. Moreover, these hybrids could strongly inhibit the activity of acetylcholinesterase and butyrylcholinesterase. Further investigations in vivo indicated that the 8-substituted hybrid 3b significantly delayed paralysis caused by Aβ1–42 toxicity in GMC101. In sum, these new hybrids could target multiple pathogenetic factors in Alzheimer’s disease and merit further investigation.

Graphical abstract

Keywords

Oxoisoaporphine derivatives Inflammation Amyloid-β aggregation Neuroprotection 

Notes

Acknowledgements

This work was supported by the National Natural Science Foundation of China (Grant No. 81260471), the Guangxi Provincial Natural Science Foundation of China (Grant No. 2013GXNSFAA019132) and the State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Guangxi Normal University (Grant No. CMEMR-C28).

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interests.

Human and animal rights

Research is not involving Human Participants and/or Animal.

Supplementary material

11030_2018_9905_MOESM1_ESM.doc (13 mb)
Supplementary material 1 (DOC 13275 kb)

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical SciencesGuangxi Normal UniversityGuilin CityChina

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