标题：Mitochondria-Targeted Lupane Triterpenoid Derivatives and Their Selective Apoptosis-Inducing Anticancer Mechanisms
作者：Ye, Yaqing; Zhang, Tao; Yuan, Huiqing; Li, Defeng; Lou, Hongxiang; Fan, Peihong
作者机构：[Ye, Yaqing; Lou, Hongxiang; Fan, Peihong] Shandong Univ, Dept Nat Prod Chem, Key Lab Chem Biol, Minist Educ,Sch Pharmaceut Sci, Jinan 250012, Shandon 更多
通讯作者地址：[Fan, PH]Shandong Univ, Dept Nat Prod Chem, Key Lab Chem Biol, Minist Educ,Sch Pharmaceut Sci, Jinan 250012, Shandong, Peoples R China.
来源：JOURNAL OF MEDICINAL CHEMISTRY
摘要：Betulin and betulinic acid have been widely studied for their anticancer activities. However, their further development is limited due to low bioavailability, poor aqueous solubility, and limited intracellular accumulation. In the present study, a triphenylphosphonium cation moiety was linked to betulin and betulinic acid to specifically target them to cancer cell mitochondria. Biological characterization established that uptake of mitochondria-targeted compound la in the mitochondria of cancer cells was increased compared to betulin. The mitochondria-targeted derivatives of betulin and betulinic acid showed stronger cytotoxicity than their parent drugs and exhibited more cytotoxic effects in cancer cells than normal cells. The mechanisms may involve the mitochondrial apoptotic pathway, probably caused by the induction of reactive oxygen species production and reducing mitochondrial membrane potential. More importantly, la significantly inhibited cancer cell proliferation and migration in an in vivo zebrafish xenograft model. Collectively, these results encourage further study of la analogs as anticancer agents.