Synthesis and bioevaluation of a series of α-pyrone derivatives as potent activators of Nrf2/ARE pathway (part I)

Xi, Meiyang; Sun, Zhong-ying; Sun, Haopeng; Jia, Jianmin; Jiang, Zhengyu; Tao, Lei; Ye, Ming; Yang, Xi; Wang, Yajing; Xue, Xiangdong; Huang, Jingjie; Gao, Yuan; Guo, Xiaoke; Zhang, Shenglie; Yang, Yingrui; Guo, Qinglong; Hu, Rong; You, Qidong

doi:10.1016/j.ejmech.2013.06.007

Cited by 26 publications

(22 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Anti-HO-1 (#5853S) were bought from Cell Signaling Technology (USA). Isolation of cell fractions and Western blotting were performed as detailed previously 44 . Briefly, the extracts were separated by SDS-PAGE and then electrotransferred to PVDF membranes (Perkin Elmer, Northwalk, CT, USA).…”

Section: Methodsmentioning

confidence: 99%

An inhibitor of the Keap1-Nrf2 protein-protein interaction protects NCM460 colonic cells and alleviates experimental colitis

Jiang

et al. 2016

Sci Rep

Self Cite

View full text Add to dashboard Cite

Ulcerative colitis (UC) is a chronic relapsing-remitting form of inflammatory bowel disease (IBD) that increases the risk of colorectal cancer, the third most common malignancy in humans. Oxidative stress is a risk factor for the development of UC. The Keap1-Nrf2-ARE pathway is one of the most important defensive mechanisms against oxidative and/or electrophilic stresses. In this study, we identified CPUY192018 as a potent small-molecule inhibitor of the Keap1-Nrf2 PPI, investigated the cyto-protective effects of CPUY192018 on the NCM460 colonic cells and evaluated whether treatment with the inhibitor of the Keap1-Nrf2 PPI exerts protection on an established experimental model of UC induced by dextran sodium sulfate (DSS). Our study clearly demonstrated that CPUY192018 had a cytoprotective effect against DSS in both NCM460 cells and mouse colon via the activation of Nrf2 signaling. These results suggested that activation of Nrf2 by directly inhibiting the Keap1-Nrf2 PPI may be beneficial as a treatment for UC.

show abstract

Section: Methodsmentioning

confidence: 99%

An inhibitor of the Keap1-Nrf2 protein-protein interaction protects NCM460 colonic cells and alleviates experimental colitis

Jiang

et al. 2016

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

“…Figure 5, the up-regulation of downstream protein NQO1 was not obvious at 8 h, which may result from the high basal level of NQO1 in HCT116 cells. 31,32 Compared to NQO1, the elevation of HO-1 and γ-GCS was much more obvious. Compound 7 doubled the expression of HO-1 and γ-GCS at the concentration of 10 μM at 8 h, while 2 only increased the expression of these two genes at 1.5-and 1.6-fold, respectively, and, at 16 h, compound 7 showed significant superiority in the elevation of NQO1, HO-1, and γ-GCS ( Figure 5 for the protein band and Figure S1 for the semiquantitative data).…”

Section: ■ Compound 7 Is More Efficacious On Up-regulating the Proteimentioning

confidence: 99%

Polar Recognition Group Study of Keap1-Nrf2 Protein–Protein Interaction Inhibitors

Tan

et al. 2016

ACS Med. Chem. Lett.

Self Cite

View full text Add to dashboard Cite

Directly disrupting the Keap1-Nrf2 protein−protein interaction (PPI) has emerged as an attractive way to activate Nrf2, and Keap1-Nrf2 PPI inhibitors have been proposed as potential agents to relieve inflammatory and oxidative stress diseases. In this work, we investigated the diacetic moiety around the potent Keap1-Nrf2 PPI inhibitor DDO1018 (2), which was reported by our group previously. Exploration of bioisosteric replacements afforded the ditetrazole analog 7, which maintains the potent PPI inhibition activity (IC 50 = 15.8 nM) in an in vitro fluorescence polarization assay. Physicochemical property determination demonstrated that ditetrazole replacement can improve the drug-like property, including elevation of pK a , log D, and transcellular permeability. Additionally, 7 is more efficacious than 2 on inducing the expression of Nrf2-dependent gene products in cells. This study provides an alternative way to replace the diacetic moiety and occupy the polar subpockets in Keap1, which can benefit the subsequent development of Keap1-Nrf2 PPI inhibitor.

show abstract

“…They synthesised a group of 3-amino-2-pyrones and performed ab iological evaluation for COX-1 inhibitoryp otential. [25] [24] Also in 2013, Xi et al synthesised and evaluated as eries of pyrone derivativesa sp otent activators of Nrf2-ARE pathway.T he literature suggest Nrf2-ARE-inducede nzymes detoxifye lectrophiles and oxidants, and thus induction of their expression by small molecules appears to be ap romising strategy for cancerp revention.…”

Section: 2 Pharmacological Profile Of Pyrone Derivativesmentioning

confidence: 99%

“…As the biphenyl compound showeda cceptable activity,i t led to the conclusion that the binding pocket was ar ather long and narrow area and that the preferred binding mode might require ap henyl substituted with some spatially small groups,s uch as halogens, or methoxy or hydroxy groups.T he authors concluded that the resulting best molecule might protect cellsa gainst oxidative stress, thus protecting cells from severalirritants. [25]…”

Section: Pharmacological Profile Of Pyrone Derivativesmentioning

confidence: 99%

The Current Status of O‐Heterocycles: A Synthetic and Medicinal Overview

Singh

Silakari

2018

ChemMedChem

View full text Add to dashboard Cite

O-Heterocycles have been explored in the field of medicinal chemistry for a long time, but their significance has not been duly recognised and they are often shunned in favour of N-heterocycles. The design of bioactive molecules for nearly every pathophysiological condition is primarily focused on novel N-heterocycles. The main reasons for such bias include the ease of synthesis and possible mimicking of physiological molecules by N-heterocycles. But considering only this criterion rarely provides breakthrough molecules for a given disease condition, and instead the risks of toxicity or side effects are increased with such molecules. On the other hand, owing to improved synthetic feasibility, O-heterocycles have established themselves as equally potent lead molecules for a wide range of pathophysiological conditions. In the last decade there have been hundreds of reports validating the fact that equally potent molecules can be designed and developed by using O-heterocycles, and these are also expected to have comparably low toxicity. Even so, researchers tend to remain biased toward the use of N-heterocycles over O-heterocycles. Thus, this review provides a critical analysis of the synthesis and medicinal attributes of O-heterocycles, such as pyrones, oxazolones, furanones, oxetanes, oxazolidinones, and dioxolonones, and others, reported in the last five years, underlining the need for and the advantages guiding researchers toward them.

show abstract

Synthesis and bioevaluation of a series of α-pyrone derivatives as potent activators of Nrf2/ARE pathway (part I)

Cited by 26 publications

References 32 publications

An inhibitor of the Keap1-Nrf2 protein-protein interaction protects NCM460 colonic cells and alleviates experimental colitis

An inhibitor of the Keap1-Nrf2 protein-protein interaction protects NCM460 colonic cells and alleviates experimental colitis

Polar Recognition Group Study of Keap1-Nrf2 Protein–Protein Interaction Inhibitors

The Current Status of O‐Heterocycles: A Synthetic and Medicinal Overview

Contact Info

Product

Resources

About