Novel sampangine derivatives as potent inhibitors of Cu2+-mediated amyloid-β protein aggregation, oxidative stress and inflammation

A series of 11-substituted sampangine derivatives have been designed, synthesized, and tested for their ability to inhibit cholinesterase. Their chelating ability and selectivity for Cu2+ over other biologically relevant metal ions were demonstrated by isothermal titration calorimetry. Their blood-brain barrier permeability was also tested by parallel artificial membrane permeation assay. Among the synthesized derivatives, compound 11 with the strong anti-acetylcholinesterase activity, high blood-brain barrier penetration ability and high binding affinity to Cu2+ was selected for further research. Western blotting analysis, transmission electron microscopy, DCFH-DA assay and paralysis experiment indicated that compound 11 suppressed the formation of Cu2+-A beta complexes, alleviated the Cu2+ induced neurotoxicity and inhibited the production of ROS catalyzed by Cu2+ in A beta 42 transgenic C elegans. Moreover, compound 11 also inhibited the expressions of proinflammatory cytokines, such as NO, TNF-alpha, IL-6 and IL-1 beta induced by Cu2+ + A beta(1-42) in BV2 microglial cells. In general, this work provided new in sights into the design and development of potent metal-chelating agents for AD treatment. (C) 2018 Elsevier B.V. All rights reserved.

Automated summary

A series of 11-substituted sampangine derivatives were designed, synthesized, and tested for their ability to inhibit cholinesterase. Among them, compound 11 showed strong anti-acetylcholinesterase activity, high blood-brain barrier penetration ability, and high binding affinity to Cu2+. Additional experiments demonstrated that compound 11 suppressed the formation of Cu2+-A beta complexes, alleviated Cu2+ induced neurotoxicity, and inhibited the production of ROS catalyzed by Cu2+ in A beta 42 transgenic C elegans. Furthermore, compound 11 also inhibited the expressions of proinflammatory cytokines induced by Cu2+ + A beta(1-42) in BV2 microglial cells.