858515-77-2Relevant academic research and scientific papers
Development and Profiling of Inverse Agonist Tools for the Neuroprotective Transcription Factor Nurr1
Zaienne, Daniel,Willems, Sabine,Schierle, Simone,Heering, Jan,Merk, Daniel
, p. 15126 - 15140 (2021/10/25)
The ligand-sensing transcription factor nuclear receptor related 1 (Nurr1) evolves as an appealing target to treat neurodegenerative diseases. Despite its therapeutic potential observed in various rodent models, potent modulators for Nurr1 are lacking as pharmacological tools. Here, we report the structure-activity relationship and systematic optimization of indole-based inverse Nurr1 agonists. Optimized analogues decreased the receptor's intrinsic transcriptional activity by up to more than 90% and revealed preference for inhibiting Nurr1 monomer activity. In orthogonal cell-free settings, we detected displacement of NCoRs and disruption of the Nurr1 homodimer as molecular modes of action. The inverse Nurr1 agonists reduced the expression of Nurr1-regulated genes in T98G cells, and treatment with an inverse Nurr1 agonist mimicked the effect of Nurr1 silencing on interleukin-6 release from LPS-stimulated human astrocytes. The indole-based inverse Nurr1 agonists valuably extend the toolbox of Nurr1 modulators to further probe the role of Nurr1 in neuroinflammation, cancer, and beyond.
A general and scalable synthesis of polysubstituted indoles
Diana-Rivero, Raquel,García-Tellado, Fernando,Tejedor, David
, (2021/06/14)
A consecutive 2-step synthesis of N-unprotected polysubstituted indoles bearing an electron-withdrawing group at the C-3 position from readily available nitroarenes is reported. The protocol is based on the [3,3]-sigmatropic rearrangement of N-oxyenamines generated by the DABCO-catalyzed reaction of N-arylhydroxylamines and conjugated terminal alkynes, and delivers indoles endowed with a wide array of substitution patterns and topologies.
A New Method for the Synthesis of 3-Substituted Indoles
Natarajan, Rakesh,Rappai, John P.,Unnikrishnan, Peruparampil A.,Radhamani, Sandhya,Prathapan, Sreedharan
supporting information, p. 2467 - 2471 (2015/10/19)
Starting from readily accessible nitrones and electron-deficient acetylenes, a highly efficient and versatile synthetic protocol for 3-substituted indoles has been developed.
