Synthesis And Anti-Alzheimer’s Disease Activity Of 8-and 11-Substituted Sampangine Derivatives

Natural sampangine alkaloids have anti-bacterial,anti-malaria,anti-inflammatory and anti-tumor activities.Because of their poor water solubility and high cytotoxicity,the development and application of these alkaloids are limited.In the paper,two series of derivatives were designed and synthesized based on sampangine alkaloids.Their anti-Alzheimer’s disease activities were tested in vitro.Eighteen 8-and 11-substituted sampangine derivatives were synthesized byα-Naphthol and N-Bromosuccinimide（NBS）and their structures were characterized by NMR and HR-MS.Their chelation abilities toward seven common metal ions(Cu²⁺、Zn²⁺、Fe³⁺、Ca²⁺、Ni²⁺、Na⁺、Mn²⁺)in human body were evaluated by Isothermal Titration Calorimetry（ITC）assay.The results showed that most of the compounds have good selectivity toward Cu²⁺,Zn²⁺,Fe³⁺.Among these compounds,7g showed the strongest binding potency toward Cu²⁺with dissociation constant（K_d）at 1.22±0.1μM and compound 7r exhibited the strongest binding potency toward Zn²⁺with dissociation constant at 0.37±0.1μM.The inhibitory potency against cholinesterase in vitro was evaluated by the method of Ellman et al.All the synthesized derivatives demonstrated much higher inhibitory potency against acetylcholinesterase（ACh E）than sampangine alkaloid,with inhibitory activity IC₅₀ values in the submicromolar range.Compounds 7e and7o exhibited highest ACh E inhibitory activity with IC₅₀ values at 47 n M and 76 n M respectively.As noted in the fact that it is 6-and 4-fold more potent than tacrine.In order to assess the potential for synthetical derivatives to penetrate the blood-brain barrier（BBB）,a parallel artificial membrane permeation assay for BBB（PAMPA-BBB）was carried out.The results showed that sampangine itself could not penetrate BBB.However,after introducing the amino group side chain into sampangine at 8 or 11-position,the derivative exhibited a very high BBB permeability with permeability coefficient P_e values ranged from 7.91×10^-6 cm·s^-1 to11.06×10^-6 cm·s^-1.It is suggested that all the derivatives could be able to cross the BBB.