Discovery of proqodine A derivatives with antitumor activity targeting NAD(P)H: quinone oxidoreductase 1 and nicotinamide phosphoribosyltransferase.
10.1016/S1875-5364(24)60564-9
- Author:
Jiangzhou SONG
1
;
Guiqing ZOU
2
,
3
;
Zhou ZHAO
1
;
Ya ZHU
1
;
Jiayu XUE
1
;
Lanjia AO
1
;
Huiyong SUN
1
;
Haiping HAO
4
;
Bo ZHANG
5
;
Xiaowei XU
6
Author Information
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, Key Lab of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China
3. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
4. State Key Laboratory of Natural Medicines, Key Lab of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China. Electronic address: haipinghao@cpu.edu.cn.
5. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China. Electronic address: zb3981444@cpu.edu.cn.
6. State Key Laboratory of Natural Medicines, Key Lab of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China. Electronic address: xw@cpu.edu.cn.
- Publication Type:Journal Article
- Keywords:
NAD(+);
NAMPT;
NQO1;
ROS;
T8
- MeSH:
Humans;
NAD/metabolism*;
Cell Line, Tumor;
Reactive Oxygen Species/metabolism*;
Nicotinamide Phosphoribosyltransferase/metabolism*;
Cytokines/metabolism*;
Quinones;
Oxidoreductases
- From:
Chinese Journal of Natural Medicines (English Ed.)
2024;22(1):75-88
- CountryChina
- Language:English
-
Abstract:
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.
