Synthesis and biological evaluation of FICZ analogues as agonists of aryl hydrocarbon receptor

Hao Wu; Binkai Liu; Ka Yang; Gabrielle N Winston-McPherson; Eric D Leisten; Chad M Vezina; William A Ricke; Richard E Peterson; Weiping Tang

doi:10.1016/j.bmcl.2020.126959

Synthesis and biological evaluation of FICZ analogues as agonists of aryl hydrocarbon receptor

Bioorg Med Chem Lett. 2020 Mar 1;30(5):126959. doi: 10.1016/j.bmcl.2020.126959. Epub 2020 Jan 7.

Authors

Hao Wu¹, Binkai Liu¹, Ka Yang¹, Gabrielle N Winston-McPherson¹, Eric D Leisten¹, Chad M Vezina², William A Ricke³, Richard E Peterson¹, Weiping Tang⁴

Affiliations

¹ School of Pharmacy, University of Wisconsin-Madison, 777 Highland Avenue, Madison, WI 53705, USA.
² Department of Comparative Biosciences, University of Wisconsin-Madison, School of Veterinary Medicine, Madison, WI 53706, USA; University of Wisconsin-Madison, O'Brien Urology Research Center, Madison, WI, USA.
³ University of Wisconsin-Madison, O'Brien Urology Research Center, Madison, WI, USA; Department of Urology and Carbone Cancer Center, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI 53705, USA.
⁴ School of Pharmacy, University of Wisconsin-Madison, 777 Highland Avenue, Madison, WI 53705, USA; Department of Chemistry, University of Wisconsin-Madison, 1101 University Avenue, Madison, WI 53706, USA. Electronic address: weiping.tang@wisc.edu.

Abstract

The aryl hydrocarbon receptor (AhR) is a ligand activated transcription factor involved in multiple biological processes including immune cell differentiation, intestinal function and inflammation. Based on the scaffold of naturally occurring AhR ligand 6-formylindolo (3,2-b) carbazole (FICZ, 2), a series of analogues has been designed, synthesized and evaluated by cell-based assays. The structure-activity relationships study has successfully led to the discovery of compound 11e with extremely potent activity.

Keywords: AhR; Benign prostatic hyperplasia; Carbazole; FICZ; Transcription factor.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Carbazoles / chemical synthesis
Carbazoles / pharmacology*
Cytochrome P-450 CYP1A1 / metabolism
Dose-Response Relationship, Drug
Hep G2 Cells
Humans
Indoles / chemical synthesis
Indoles / pharmacology*
Molecular Structure
Receptors, Aryl Hydrocarbon / agonists*
Structure-Activity Relationship
Up-Regulation / drug effects

Substances

Carbazoles
Indoles
Receptors, Aryl Hydrocarbon
CYP1A1 protein, human
Cytochrome P-450 CYP1A1

Abstract

Publication types

MeSH terms

Substances

Grants and funding