The Synthesis Of Evodiamine Derivatives And Preliminary Evaluation Of The Pharmacodynamics And Pharmacokinetics

Evodia is the nearly dried ripe fruit of Rutaceae Evodia,tigers or sparsely hairy evodia.Which has regulate immunity,inhibit obesity,anti-tumor,anti-inflammatory and analgesic pharmacological activitives.Evodiamine(EVO)is one of the effective components.However,the lower extraction rate of the active ingredient from Evodia,and the poor water-soluble evodiamine lipophilic defects,which difficults to further study and greatly limits the evodiamine in a wide range of clinical applications.By modifying the structure of evodiamine,10-nitro evodiamine derivative ENO and 10-amino evodiamine derivative ENH were synthesized.Solubility and partition coefficient of derivatives were determined;CCK-8 assay detected the pharmacodynamic activity of two derivatives;Observe the pharmacokinetic behaviors in rats,and observed in rats pharmacokinetic behaviors after oral ENO and ENH.Compared with EVO,study the kinetics and pharmacokinetic of ENO and ENH.The main works includes the following parts:Based on the traditional Chinese medicine extracts EVO,10-substituted derivatives evodiamine ENO and ENH were synthesized.The effects of the molar ratio of EVO,H2SO4 and KNO3,reaction time,temperature and recrystallization solvent on the yield were investigated.Under the following optimal reaction condition:1)ENO;nEVO: nH2SO4: nKNO3=1:56:1,reaction time was 0.5h,reaction temperature was-10?,recrystallization solvent was H2O:DMF=1:4(V / V).2)ENH;the ratio of ENO and methanol was 1: 300(g / mL),the reaction temperature was 45?,reaction time was 6.5 h,pressure was 1.8~1.9 MPa.The structure of the target products were confirmed by MS and 1HNMR,which indated ENO and ENH synthesized successfully.The solubility of ENO and ENH in water were 0.22 ?g / mL and 20.75 ?g / mL,oil-water partition coefficients were 1.22 and 1.30.Compared with EVO,ENO's solubility increased slightly,while ENH's solubility increased about 121 times;the oil-water partition coefficient of ENO and ENH increased about 2 times.The pharmacodynamic test results of ENO and ENH showed that ENH can inhibit the tumor cells proliferation close to 100 % at the concentration of 3 ?M and 72 h compare with EVO,while anti-tumor activity of ENO was reduced 10 %.Rats pharmacokinetic study results showed that,with respect to the EVO,ENO pharmacokinetic properties change was not obvious;CL of ENH was lower,the area under the concentration-time curve increased,Cmax increased,AUC0-t and absorption increased significantly.