Quinone reductase 2 (QR2) is an enzyme which recognizes putative metabolites of NADH, such as N-methyl- and N-ribosyl-dihydronicotinamide. It has been particularly associated with reactive oxygen species and memory, strongly suggesting a link among QR2 (as a possible key element in pro-oxidation), autophagy, and neurodegeneration[1]. S29434 is a potent, nanomolar inhibitor of QR2 with IC50 of 5-16 nM at different organizational levels[1]. Paraquat (PQ) (30 mg/kg) and S29434 were administered i.p. to Wistar rats and animals were monitored for 28 days. S29434 potently antagonized non-apoptotic PQ-induced cell death, reactive oxygen species (ROS) generation and inhibited cellular QR2 activity. Significantly, S29434 (4.5 mg/kg) potently antagonized PQ-induced systemic toxicity and animal mortality. Microinfusion of S29434 into substantia nigra (SN) prevented severe behavioural and electrocortical effects of PQ which correlated with inhibition of malondialdehyde accumulation in cells and tissues[2].
作用机制
S29434 fits deeply into a QR2 hydrophobic cavity (Protein Data Bank: 3OX3), interacting with subunits A and B with its amido-furan side chains pointing toward the solvent.
S29434 细胞实验
Cell Line
Concentration
Treated Time
Description
References
SH-SY5Y cells
10 µM
24 hours
No protective effect observed against 6OHDA-induced cell death
Sci Rep. 2023 Dec 7;13(1):21624
Healthy RBCs
20 µM
30 min
Inhibited hQR2 activity and reduced radical production
Confirmed low endogenous QR2 levels with minimal inhibition by S29434
Molecules. 2017 Jan 30;22(2):210
Primary murine astrocytes
10 µM
24 hours
Restored 6OHDA-induced inhibition of autophagic flux and partially reduced oxidative stress
Sci Rep. 2023 Dec 7;13(1):21624
U373 cells
10 µM
24 hours
Restored 6OHDA-induced inhibition of autophagic flux and partially reduced oxidative stress
Sci Rep. 2023 Dec 7;13(1):21624
Rat embryonic hippocampal neurons
1–30 µM
24 hours
To evaluate the protective effect of S29434 against menadione-induced cytotoxicity, results showed that S29434 reversed the proapoptotic action of menadione and protected hippocampal neurons from cell death.
J Neurosci. 2010 Sep 22;30(38):12690-700
HT-22 cells
1–50 µM
30 min
Evaluate the effect of S29434 on ROS production in HT-22 cells, showing that S29434 at 25 and 50 µM significantly reduces ROS production.
Int J Mol Sci. 2021 Dec 2;22(23):13061
HT-22 cells
1-50 µM
30 min
The NQO2 inhibitor S29434 significantly reduced the percentage of comet-tail DNA in the whole range of concentrations
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