Zou_2021_Int.J.Biol.Macromol__

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(2+) 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(2+) 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(2+)-Abeta complexes, alleviated the Cu(2+) induced neurotoxicity and inhibited the production of ROS catalyzed by Cu(2+) in Abeta42 transgenic C. elegans. Moreover, compound 11 also inhibited the expressions of proinflammatory cytokines, such as NO, TNF-alpha, IL-6 and IL-1beta, induced by Cu(2+) + Abeta(1-42) in BV2 microglial cells. In general, this work provided new insights into the design and development of potent metal-chelating agents for AD treatment.