Synthesis And Anti-Alzheimer’s Disease Activity Of 4-Substituted Sampangine Derivatives

The sampangine alkaloids were first extracted from Cananga odorata(Lamk.)Hook.f.et Thoms.It was reported that sampangine alkaloids had strong anti-tumor,anti-malaria,anti-inflammatory and other pharmacological activities,and it can be used as leading compounds for anti-tumor and anti-malaria.Because of its poor water solubility and cell toxicity,the development and application of sampangine alkaloids were limited.By modifying its structure,we hope to improve its disadvantages,and lay the foundation for the follow-up study of sampangine derivatives.In this paper,sampangine alkaloid was synthesized by α-naphthol and N-bromosuccinimide Alkylamino were introduced to sampangine on 4-substituents.Finally,eight novels 4-substituted sampangine derivatives were obtained.Their inhibitory activity of cholinesterase and Aβ42 aggregation and the cytotoxicity of neuroblastoma cells and blood brain barrier permeability in vitro were evaluated.The main results are as following:(1)Sampangine alkaloid has no inhibitory effect toward cholinesterase.All the synthesized derivatives demonstrated much higher inhibitory potency against acetylcholinesterase(AChE)than sampangine.The IC50 values of synthesized compounds ranged between 0.23 μM and 13.60μM.Compound 10 had the strongest inhibitory activity.(2)Sampangine alkaloid has a greater cytotoxicity toward SH-SY5Y cell.Introducing the side chain in sampangine alkaloid greatly reduced its toxicity.(3)After treatment with derivatives,APPsw cells showed various degrees of reducing the Aβ42 secretion level.Moreover,the decrease was concentration dependent.The Aβ42 secretion level always decreased with the increase of derivatives concentration.(4)Most of the derivaties could be able to cross the blood-brain barrier(CNS+).The alkylamino side chains were first introduced to sampangine on 4-substitution.It not only increased the water solubility of the derivatives,but also reduced their toxicity.Especially for compound 10,it had the strongest anti-cholinesterase and anti-Aβ aggregating activity but its toxicity was weakest.4-substituted sampangine derivatives are expected to be a new anti-AD candidate drugs,which is worthy of being further research.