155338-73-1Relevant academic research and scientific papers
Inhibitors of the protein–protein interaction between phosphorylated p62 and Keap1 attenuate chemoresistance in a human hepatocellular carcinoma cell line
Yasuda, Daisuke,Ohe, Tomoyuki,Takahashi, Kyoko,Imamura, Riyo,Kojima, Hirotatsu,Okabe, Takayoshi,Ichimura, Yoshinobu,Komatsu, Masaaki,Yamamoto, Masayuki,Nagano, Tetsuo,Mashino, Tadahiko
, p. 859 - 871 (2020)
Resistance to anticancer agents has been an obstacle to developing therapeutics and reducing medical costs. Whereas sorafenib is used for the treatment of human hepatocellular carcinoma (HCC), resistance limits its efficacy. p62, a multifunctional protein, is overexpressed in several HCC cell lines, such as Huh-1 cells. Phosphorylated p62 (p-p62) inhibits the protein–protein interaction (PPI) between Keap1 and Nrf2, resulting in the Nrf2 overactivation that causes drug resistance. We have found a unique Nrf2 inactivator, named K67, that inhibited the PPI between Keap1 and p-p62 and attenuated sorafenib resistance in Huh-1 cells. Herein, we designed and synthesised novel K67 derivatives by modification of the substituent at the 4-position of the two benzenesulfonyl groups of K67. Although these new derivatives inhibited the Keap1-p-p62 PPI to a level comparable to or weaker than that of K67, the isopropoxy derivative enhanced the sensitivity of Huh-1 cells to sorafenib to a greater extent than K67 without any influence on the viability of Huh-7 cells, which is a non-resistant HCC cell line. The isopropoxy derivative also increased the sensitivity of Huh-1 cells to regorafenib, which suggests that this derivative has the potential to be used as an agent to overcome chemoresistance based on Nrf2 inactivation.
Structure-Activity and Structure-Property Relationship and Exploratory in Vivo Evaluation of the Nanomolar Keap1-Nrf2 Protein-Protein Interaction Inhibitor
Jiang, Zheng-Yu,Xu, Li-Li,Lu, Meng-Chen,Chen, Zhi-Yun,Yuan, Zhen-Wei,Xu, Xiao-Li,Guo, Xiao-Ke,Zhang, Xiao-Jin,Sun, Hao-Peng,You, Qi-Dong
, p. 6410 - 6421 (2015/09/08)
Directly disrupting the Keap1-Nrf2 protein-protein interaction (PPI) is an effective way to activate Nrf2. Using the potent Keap1-Nrf2 PPI inhibitor that was reported by our group, we conducted a preliminary investigation of the structure-activity and structure-property relationships of the ring systems to improve the drug-like properties. Compound 18e, which bore p-acetamido substituents on the side chain phenyl rings, was the best choice for balancing PPI inhibition activity, physicochemical properties, and cellular Nrf2 activity. Cell-based experiments with 18e showed that the Keap1-Nrf2 PPI inhibitor can activate Nrf2 and induce the expression of Nrf2 downstream proteins in an Nrf2-dependent manner. An exploratory in vivo experiment was carried out to further evaluate the anti-inflammatory effects of 18e in a LPS-challenged mouse model. The primary results indicated that 18e could reduce the level of circulating pro-inflammatory cytokines induced by LPS and relieve the inflammatory response. (Chemical Equation Presented).
Probing the structural requirements of non-electrophilic naphthalene-based Nrf2 activators
Jain, Atul D.,Potteti, Haranatha,Richardson, Benjamin G.,Kingsley, Laura,Luciano, Julia P.,Ryuzoji, Aya F.,Lee, Hyun,Krunic, Aleksej,Mesecar, Andrew D.,Reddy, Sekhar P.,Moore, Terry W.
, p. 252 - 268 (2015/09/21)
Activation of the transcription factor Nrf2 has been posited to be a promising therapeutic strategy in a number of inflammatory and oxidative stress diseases due to its regulation of detoxifying enzymes. In this work, we have developed a comprehensive structure-activity relationship around a known, naphthalene-based non-electrophilic activator of Nrf2, and we report highly potent non-electrophilic activators of Nrf2. Computational docking analysis of a subset of the compound series demonstrates the importance of water molecule displacement for affinity, and the X-ray structure of di-amide 12e supports the computational analysis. One of the best compounds, acid 16b, has an IC50 of 61 nM in a fluorescence anisotropy assay and a Kd of 120 nM in a surface plasmon resonance assay. Additionally, we demonstrate that the ethyl ester of 16b is an efficacious inducer of Nrf2 target genes, exhibiting ex vivo efficacy similar to the well-known electrophilic activator, sulforaphane.
SYNTHESIS OF UNSYMMETRICAL 1,4-NAPHTHOQUINONE DIIMIDES
Matevosyan, K. R.,Lokmane, E. Ya.,Freimanis, Ya. F.
, p. 834 - 839 (2007/10/02)
The reaction of 4-nitronaphthylamine with methane-, benzene-, and p-toluenesulfonyl chlorides in pyridine gave N,N-diacyl-4-nitronaphthylamines, which were converted by alkaline hydrolysis into N-acyl-4-nitronaphthylamines.With benzoyl chloride the reacti
