Synthesis Of Mitochondria-targeted Triptolide Derivatives And Their Antitumor Activities

Tumor is a serious threat to human health and quality of life.Tumor cells are characterized by immortality(unlimited proliferation),migration and the disappearance of contact inhibition.Mitochondrion is an important energy metabolism and biosynthesis factory,which is very important for the normal function of cells and human health.The mitochondria of tumor cells are obviously different from those of normal cells.The special performance of tumor cells is closely related to the abnormal function of mitochondria.Nowadays,cancer is also considered as a mitochondrial metabolic disease,and mitochondria become an important target for antitumor treatmentRelated studies have shown that the mitochondrial membrane potential of tumor cells is much higher than that of normal cells.Electron delocalized lipophilic cationic compounds(DLCs)can selectively accumulate in the mitochondria of tumor cells by taking advantage of the difference of tumor cell membrane potential.Small antitumor molecules can be linked with DLCs as mitochondria targeted compounds to achieve certain tumor cell selectivity and enhance anti-tumor effect.Triphenylphosphine(TPP+)is one of the most widely used and studied DLCs.Its function of targeting mitochondria has been confirmed by many literatures.Triptolide(TP)is a natural antitumor component from the root of the Chinese medicinal herb Tripterygium wilfordii Hook.f.However,due to its poor water solubility,high systemic toxicity and narrow treatment window,it can not be used widely in clinic.In order to investigate whether the mitochondrial targeting property of TPP+can improve the antitumor activity of TP,increase its selectivity to tumor cells and reduce its toxicity,TPP+derivatives of TP were designed and synthesized in this paper,and their antitumor activities in vitro and in vivo were evaluatedAfter activity screening,we found that among the five TPP+ derivatives of TP,Mito-TP-2 not only maintained the antitumor activity of TP,but also showed tumor cell selectivity between normal liver cells HL-7702 and hepatocellular carcinoma cells HepG-2.The accumulation of Mito-TP-2 in HepG-2 cells determined by RP-HPLC is three times as much as TP,indicating certain mitochondrial targeting property.Further experiments showed that Mito-TP-2 could increase the release of LDH,the production of ROS and decrease the mitochondrial membrane potential,as well as arrest the HepG-2 cells in G0/G1 phase.In zebrafish HepG-2 xenograft tumor model,the inhibitory effect of Mito-TP-2(1 ?M)is comparable to TP,while it has no obvious toxic effect(pericardial edema)on zebrafish juveniles as TP.The toxicity test of compounds TP and Mito-TP-2 also showed that TP was teratogenic in the low concentration group,and the hatching rate and body length decreased with the increase of concentration.Meanwhile,TP had obvious liver toxicity.However,no obvious toxicity was found in the same dose groups of Mito-TP-2.It was found that pericardial edema occurred occasionally only when the concentration of Mito-TP-2 was as high as 12 ?M.When the concentration was less than 12 ?M,Mito-TP-2 had no obvious effect on the mortality,hatching rate,deformity rate and body length of zebrafish,indicating that Mito-TP-2 can reduce the toxicity of TP while maintain its antitumor activityThis paper is an attempt in drug development based on natural products to maintain the antitumor effect of TP while reducing its toxicity,which provides some basis and thoughts for further research.