Skip Navigation
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

National Institute of Environmental Health Sciences

Use this QR code to view the newest version of this document
Use this QR code to view the newest version of this document

Your Environment. Your Health.

Publication Detail

Title: Structure-dependent activation of gene expression by bis-indole and quinoline-derived activators of nuclear receptor 4A2.

Authors: Li, Xi; Tjalkens, Ronald B; Shrestha, Rupesh; Safe, Stephen

Published In Chem Biol Drug Des, (2019 10)

Abstract: Bis-indole derivatives including 1,1-bis(3'-indolyl)-1-(4-chlorophenyl)methane (DIM-C-pPhCl) and substituted quinolines such as chloroquine (CQ) and amodiaquine (AQ) are nuclear receptor 4A2 (NR4A2, Nurr1) ligands, and they exhibit anti-inflammatory activities in mouse and rat models of Parkinson's disease, respectively. However, computational modeling demonstrates that the quinoline derivatives interact with the ligand-binding domain, whereas the bis-indoles preferentially interact with a C-terminal cofactor binding site of NR4A2. In this study, the effects of DIM-C-pPhCl and related analogs were compared with CQ/AQ as inducers of NR4A2-responsive genes including vasoactive intestinal peptide, osteopontin, proopiomelanocortin, and neuropilin 1 in Panc1 and Panc28 pancreatic cancer cells. The results demonstrate that, among the bis-indole analogs, their relative potencies as inducers were structure-gene- and cell context dependent. In contrast, CQ and AQ were significantly less potent than the bis-indole derivatives and, for some of the NR4A2-regulated genes, CQ and AQ were inactive as inducers. These results demonstrate that although bis-indole and quinoline derivatives have been characterized as activators of NR4A2-dependent gene expression, these two classes of compounds exhibit different activities, indicating that they are selective NR4A2 modulators.

PubMed ID: 31102570 Exiting the NIEHS site

MeSH Terms: Animals; Cell Line, Tumor; Gene Expression Regulation, Neoplastic/drug effects*; Humans; Indoles*/chemical synthesis; Indoles*/chemistry; Indoles*/pharmacology; Mice; Neoplasm Proteins/metabolism*; Nuclear Receptor Subfamily 4, Group A, Member 2/agonists*; Nuclear Receptor Subfamily 4, Group A, Member 2/metabolism; Pancreatic Neoplasms/metabolism*; Pancreatic Neoplasms/pathology; Quinolines*/chemical synthesis; Quinolines*/chemistry; Quinolines*/pharmacology; Rats; Structure-Activity Relationship

Back
to Top