Discovery of proqodine A derivatives with antitumor activity targeting NAD(P)H:quinone oxidoreductase 1 and nicotinamide phosphoribosyltransferase  

作　　者：SONG Jiangzhou ZOU Guiqing ZHAO Zhou ZHU Ya XUE Jiayu AO Lanjia SUN Huiyong HAO Haiping ZHANG Bo XU Xiaowei 

机构地区：[1]State Key Laboratory of Natural Medicines,Key Lab of Drug Metabolism and Pharmacokinetics,China Pharmaceutical University,Nanjing 210009,China [2]State Key Laboratory of Natural Medicines,China Pharmaceutical University,Nanjing 210009,China

出　　处：《Chinese Journal of Natural Medicines》2024年第1期75-88,共14页中国天然药物（英文版）

基　　金：This work was supported by the National Key Research and Development Programme of China(No.YFA1303800);the Fundamental Research Funds for the Central Universities(No.2632023TD10);the National Natural Science Foundation of China(No.81930109).

摘　　要：NAD(P)H:quinone oxidoreductase 1(NQO1)is a flavin protease highly expressed in various cancer cells.NQO1 catalyzes a futile redox cycle in substrates,leading to substantial reactive oxygen species(ROS)production.This ROS generation results in extensive DNA damage and elevated poly(ADP-ribose)polymerase 1(PARP1)-mediated consumption of nicotinamide adenine dinucleotide(NAD^(+)),ultimately causing cell death.Nicotinamide phosphoribosyltransferase(NAMPT),the rate-limiting enzyme in the NAD^(+)salvage synthesis pathway,emerges as a critical target in cancer therapy.The concurrent inhibition of NQO1 and NAMPT triggers hyperactivation of PARP1 and intensive NAD+depletion.In this study,we designed,synthesized,and assessed a novel series of proqodine A derivatives targeting both NQO1 and NAMPT.Among these,compound T8 demonstrated potent antitumor properties.Specifically,T8 selectively inhibited the proliferation of MCF-7 cells and induced apoptosis through mechanisms dependent on both NQO1 and NAMPT.This discovery offers a promising new molecular entity for advancing anticancer research.

关 键 词：NQO1 ROS NAMPT NAD^(+) T8 

分 类 号：R284[医药卫生—中药学] R965[医药卫生—中医学]