Extraction Of Pseudopelletierine And The Synthesis、Application Of Related Derivatives

Pseudopelletierine is an important alkaloid which exists in the pomegranate stem bark,root bark and pericarp. Pseudopelletierine has a unique9-azabicyclo [3.3.1] nonane structurewhich is the analogue of tropinone and main skeleton of some active substances. However,the studies on pseudopelletierine is much less than tropinone. Researches onpseudopelletierine derivatives are mainly focused on a series of granisetron derivatives anddopamine receptor gene. Therefore, the investigation on pseudopelletierine extraction,pseudopelletierine and derivatives synthesis, the activities has important theoreticalsignificance and application value.Firstly, the extraction process of pseudopelletierine from pomegranate peel was studiedwith the organic solvent, aqueous hydrochloric acid, ultrasonic and microwave extractionmethods respectively in this paper. Then, the pseudopelletierine was synthesized via theRobinson-Sch pf reaction. The effects of reaction time, solvent, amount of alkali, alkalispecies and reaction temperature on the yield were investigated and the optimum reactioncondition was obtaied. When the reaction was carried out in water at room temperature with1equiv of Na2HPO4·12H2Othrough24h, the yield is up to92.6%. Additionally, a total of22pseudopelletierine derivatives were synthesized and the structures were characterized. At thesame time, we firstly reported the crystal structure of (1S*,5R*)-9-Phenyl-9-azabicyclo[3.3.1]nonan-3-one. Finally, we explored the application ofpseudopelletierine and its derivatives. On one hand, a preliminary study on biological activityof the above compounds was carried out. The MTT method was used to determine thepseudopelletierine derivatives inhibitory activity on the proliferation of tumor cells in vitro.The experiment results showed that these derivatives have significantly inhibitory activity atonly higher concentration (0.1um). Through computer aided molecular docking, thesecompounds were docked with the P-glycoprotein and MRP1. The results showed thatpseudopelletierine derivatives may have potential multidrug resistance of tumorous cells andthese compounds may be used as a candidate compounds of chemotherapy sensitizing agent.On the other hand, pseudopelletierine alcohol analogues and thiourea/urea compounds werefirstly applied to catalyze the MBH reaction, which can achieve the moderate to good yield.