Discovered in 1998 as a member of ligand-activated transcription factors, Pregnane X Receptor (PXR, NR1I2) plays a key role in metabolic detoxification systems by sensing the presence of xenobiotics and triggering detoxification responses. Moreover, PXR regulates immune/inflammatory responses, cell proliferation, bile acid/cholesterol homeostasis, glucose and lipid metabolism, and steroid/endocrine homeostasis. Recent findings suggest that PXR is also required for maintaining healthy commensalism between microbiota and gut. In view of the multiple roles in various physiological processes, targeting PXR in relevant human diseases represents one of the most promising and challenging approaches for developing novel therapeutic strategies. To validate PXR as clinically relevant and druggable target, it is therefore crucial to discover and develop small molecules that specifically bind and modulate PXR-mediated pathways. As a continuation of our ongoing research programmes towards the development of steroid-responsive nuclear receptor modulators,3 herein we report the design and implementation of a multicomponent flow-assisted synthesis for the preparation of a focused library of tetrahydroquinolines. Moreover, the preliminary results of in vitro biological evaluations of the synthesized compounds as PXR ligands will be also reported and discussed.
IDENTIFICATION OF A NOVEL CLASS OF PREGNANE X RECEPTOR (PXR) LIGANDS: FLOW SYNTHESIS AND PRELIMINARY BIOLOGICAL ACTIVITY OF TETRAHYDROQUINOLINES
Cerra, Bruno;MACCHIARULO, Antonio;GIOIELLO, ANTIMO
2016
Abstract
Discovered in 1998 as a member of ligand-activated transcription factors, Pregnane X Receptor (PXR, NR1I2) plays a key role in metabolic detoxification systems by sensing the presence of xenobiotics and triggering detoxification responses. Moreover, PXR regulates immune/inflammatory responses, cell proliferation, bile acid/cholesterol homeostasis, glucose and lipid metabolism, and steroid/endocrine homeostasis. Recent findings suggest that PXR is also required for maintaining healthy commensalism between microbiota and gut. In view of the multiple roles in various physiological processes, targeting PXR in relevant human diseases represents one of the most promising and challenging approaches for developing novel therapeutic strategies. To validate PXR as clinically relevant and druggable target, it is therefore crucial to discover and develop small molecules that specifically bind and modulate PXR-mediated pathways. As a continuation of our ongoing research programmes towards the development of steroid-responsive nuclear receptor modulators,3 herein we report the design and implementation of a multicomponent flow-assisted synthesis for the preparation of a focused library of tetrahydroquinolines. Moreover, the preliminary results of in vitro biological evaluations of the synthesized compounds as PXR ligands will be also reported and discussed.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
