Quassinoids Against Pancreatic Cancer From Bruceae Fructus And Their Mitochondrial Targeting Derivatization

The study is a portion of the National Natural Science Foundation of China(No.81773876).Pancreatic cancer is highly malignant,and the global incidence has been increasing in recent years.The choice and effectiveness of clinical drugs are limited.Therefore,new anti-pancreatic cancer drugs with low toxicity and high efficiency are urgent.Our previous studies showed that quassinoids of Bruceae Fructus possessed significant anticancer activity against pancreatic cancer and identified the basic structural skeleton for quassinoids bearing potent antitumor activities.Here,this promising result inspired us to search for anti-pancreatic cancer lead compounds from the Brucea javanica based on the common structure and modify their structures.We identified sixteen quassinoids,including an undescribed C22-quassinoid named sergeolide A(1)and two quassinoids desmethyl-bruceine B(2)and desmethyl-bruceine C(3)for which NMR data have never been reported.In vitro anti-pancreatic cancer effects of these compounds were evaluated by MTT assays,and quassinoids with high anti-pancreatic cancer activity were found,including brusatol(IC50=0.034 μM),bruceine A(IC50=0.029 μM)and 3’hydroxybruceine A(IC50=0.054 μM).Based on the principle of mitochondrial targeting design in tumor cells,we carried out structural derivatization studies around brusatol.Eleven compounds were synthesized by conjugating triphenylphosphonium cation as a carrier to brusatol.In vitro assay,we found that compound 19 selectively target tumor cell mitochondria while maintaining brusatol activity.Further experiments showed that compound 19 induced tumor cell apoptosis,increased the production of ROS,and decreased mitochondrial membrane potential.In addition,the structure-activity relationship of brusatol derivatives,the clinical treatment status of pancreatic cancer and the research status of mitochondrial-targeted drugs were systematically reviewed.The study provides a certain reference for the research of new anti-pancreatic cancer drugs and the high-value utilization of Brucea javanica.