2243-61-0Relevant articles and documents
Unravelling the mechanism of cobalt-catalysed remote C-H nitration of 8-aminoquinolinamides and expansion of substrate scope towards 1-naphthylpicolinamide
Chu, Melody,Planas, Oriol,Company, Anna,Ribas, Xavi,Hamilton, Alex,Whiteoak, Christopher J.
, p. 534 - 542 (2020)
Previously, an unexpected Co-catalysed remote C-H nitration of 8-aminoquinolinamide compounds was developed. This report provided a novel reactivity for Co which was assumed to proceed through the mechanistic pathway already known for analogous Cu-catalysed remote couplings of the same substrates. In order to shed light into this intriguing, and previously unobserved reactivity for Co, a thorough computational study has now been performed, which has allowed for a full understanding of the operative mechanism. This study demonstrates that the Co-catalysed remote coupling does not occur through the previously proposed Single Electron Transfer (SET) mechanism, but actually operates through a high-spin induced remote radical coupling mechanism, through a key intermediate with significant proportion of spin density at the 5- and 7-positions of the aminoquinoline ring. Additionally, new experimental data provides expansion of the synthetic utility of the original nitration procedure towards 1-naphthylpicolinamide which unexpectedly appears to operate via a subtly different mechanism despite having a similar chelate environment.
Design, Synthesis, and Initial Evaluation of Affinity-Based Small-Molecule Probes for Fluorescent Visualization and Specific Detection of Keap1
Lu, Mengchen,Zhou, Hai-Shan,You, Qi-Dong,Jiang, Zhengyu
, p. 7305 - 7310 (2016)
Keap1 is a pluripotent protein which plays a predominant role in cellular homeostasis and stress responses. Given that the cellular environment is quite dynamic and versatile, further investigation of the function of Keap1 depends on tools for specific and real-time detection of Keap1. Herein, we report the development of functional affinity-based small-molecule probes which can overcome some shortcomings of current methods and be applied in further studying the function of Keap1.
Deconstructing Noncovalent Kelch-like ECH-Associated Protein 1 (Keap1) Inhibitors into Fragments to Reconstruct New Potent Compounds
Pallesen, Jakob S.,Narayanan, Dilip,Tran, Kim T.,Solbak, Sara M. ?.,Marseglia, Giuseppe,S?rensen, Louis M. E.,H?j, Lars J.,Munafò, Federico,Carmona, Rosa M. C.,Garcia, Anthony D.,Desu, Haritha L.,Brambilla, Roberta,Johansen, Tommy N.,Popowicz, Grzegorz M.,Sattler, Michael,Gajhede, Michael,Bach, Anders
, p. 4623 - 4661 (2021/05/07)
Targeting the protein-protein interaction (PPI) between nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1) is a potential therapeutic strategy to control diseases involving oxidative stress. Here, six classes of known small-molecule Keap1-Nrf2 PPI inhibitors were dissected into 77 fragments in a fragment-based deconstruction reconstruction (FBDR) study and tested in four orthogonal assays. This gave 17 fragment hits of which six were shown by X-ray crystallography to bind in the Keap1 Kelch binding pocket. Two hits were merged into compound 8 with a 220-380-fold stronger affinity (Ki = 16 μM) relative to the parent fragments. Systematic optimization resulted in several novel analogues with Ki values of 0.04-0.5 μM, binding modes determined by X-ray crystallography, and enhanced microsomal stability. This demonstrates how FBDR can be used to find new fragment hits, elucidate important ligand-protein interactions, and identify new potent inhibitors of the Keap1-Nrf2 PPI.
Keap1-Nrf2 PPI inhibitor prodrug and preparation method and application
-
Paragraph 0031; 0034-0037; 0042; 0043, (2021/02/06)
The invention discloses a Keap1-Nrf2 PPI inhibitor prodrug and a preparation method and application. According to the prodrug P-168 provided by the invention, a polar carboxylic acid group of an active compound 168 is blocked, so that the fat solubility is improved, and the membrane permeability and druggability are effectively improved; the prodrug P-168 is reduced under the condition of high ROS, a pharmacophore 168 and a fluorophore coumarin are released, expression of Nrf2 and downstream genes of Nrf2 is activated, anti-inflammatory activity is brought into play, and meanwhile fluorescenceis released to achieve visual monitoring.
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 (2020/04/01)
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.
