Identification of Novel Indole Derivatives Acting As Inhibitors of the Keap1-Nrf2 Interaction

Overview

Journal J Enzyme Inhib Med Chem

Specialty Biochemistry

Date 2019 Jun 11

PMID 31179771

Citations 7

Authors

Barbara Cosimelli

Giovanni Greco

Sonia Laneri

Ettore Novellino

Antonia Sacchi

Giorgio Amendola

Sandro Cosconati

Roberta Bortolozzi

Giampietro Viola

Affiliations

Soon will be listed here.

Abstract

Nine indole derivatives () were tested as potential inhibitors of the Keap1-Nrf2 interaction. This class of compounds increases the intracellular levels of the transcription factor Nrf2 and the consequent expression of enzymes encoded by genes containing the antioxidant response element (ARE). In the ARE-luciferase reporter assay only - revealed to be remarkably more active than -butylhydroxyquinone (-BHQ), with standing out as the best performing compound. While and are weak acids, is an ampholyte prevailing as a zwitterion in neutral aqueous solutions. The ability of to significantly increase levels of Nrf2, NADPH:quinone oxidoreductase 1, and transketolase (TKT) gave further support to the hypothesis that these compounds act as inhibitors of the Keap1-Nrf2 interaction. Docking simulations allowed us to elucidate the nature of the putative interactions between and Keap1.

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