Synthesis of Piperlongumine Analogues and Discovery of Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) Activators as Potential Neuroprotective Agents

Abstract

The cellular antioxidant system plays key roles in blocking or retarding the pathogenesis of adult neurodegenerative disorders as elevated oxidative stress has been implicated in the pathophysiology of such diseases. Molecules with the ability in enhancing the antioxidant defense thus are promising candidates as neuroprotective agents. We reported herein the synthesis of piperlongumine analogues and evaluation of their cytoprotection against hydrogen peroxide- and 6-hydroxydopamine-induced neuronal cell oxidative damage in the neuron-like PC12 cells. The structure-activity relationship was delineated after the cytotoxicity and protection screening. Two compounds (4 and 5) displayed low cytotoxicity and confer potent protection of PC12 cells from the oxidative injury via upregulation of a panel of cellular antioxidant molecules. Genetically silencing the transcription factor Nrf2, a master regulator of the cellular stress responses, suppresses the cytoprotection, indicating the critical involvement of Nrf2 for the cellular action of compounds 4 and 5 in PC12 cells.

A specific fluorescent probe reveals compromised activity of methionine sulfoxide reductases in Parkinson's disease

“…6-Hydroxydopamine (6-OHDA) is a well-established neurotoxin used to generate PD models in animals or cells. 45,46 We employed the 6-OHDA-treated PC 12 cells as a cellular model of PD 47–49 and applied Msr-blue to probe the function of Msrs in the cells. As illustrated in Fig.…”

Reversing ROS‐mediated neurotoxicity by chlorogenic acid involves its direct antioxidant activity and activation of Nrf2‐ARE signaling pathway

“…PCR primers specific to each gene are as follows: GAPDH: 5 0 -cagtgccagcctcgtctcat-3 0 and 5 0 -aggggccatccacagtcttc-3 0 ; heme oxygenase-1 (HO-1): 5 0 -gccctggaagaggagatagag-3 0 and 5 0 -tagtgctgtgtggctggtgt-3 0 ; NQO1: 5 0 -tcaccactctactttgctccaa-3 0 and 5 0 -ttttctgctcctcttgaacctc-3 0 ; Trx1: 5 0 -ccttctttcattccctctgtgac-3 0 and 5 0 -cccaaccttttgaccctttttat-3 0 ; TrxR1: 5 0 -actgctcaatccacaaacagc-3 0 and 5 0 -ccacggtctctaagccaatagt-3 0 . Target genes' expression was measured and normalized to the GAPDH expression level [34,40].…”

Molecular similarity guided optimization of novel Nrf2 activators with 1,2,4-oxadiazole core

“…In the following activity evaluation, it was found that compound 7 promoted Nrf2 translocation into the nuclei and up-regulated the expression of c-GCS, NQO1, HO-1. These downstream proteins, NQO1, c-GCS and HO-1 29,30 Both in HCT116 and normal cells, 7 did not show cytotoxicity. What is more, it displayed cell protection in three normal cells such as L02, NCM460 and PC12 cells against H 2 O 2 damage.…”