Novel sampangine derivatives as potent inhibitors of Cu-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 Cu 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 Cu 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 Cu-Aβ complexes, alleviated the Cu induced neurotoxicity and inhibited the production of ROS catalyzed by Cu in Aβ42 transgenic C. elegans. Moreover, compound 11 also inhibited the expressions of proinflammatory cytokines, such as NO, TNF-α, IL-6 and IL-1β, induced by Cu + Aβ in BV2 microglial cells. In general, this work provided new insights into the design and development of potent metal-chelating agents for AD treatment.