Abstract
Nine indole derivatives (9a-i) 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 9e-g revealed to be remarkably more active than t-butylhydroxyquinone (t-BHQ), with 9g standing out as the best performing compound. While 9e and 9f are weak acids, 9g is an ampholyte prevailing as a zwitterion in neutral aqueous solutions. The ability of 9e-g 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 9g and Keap1.
Highlights
The interaction between Kelch-like ECH-associated protein 1 (Keap1)[1] and the Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2)[2] plays a crucial role in the homeostasis of cellular oxidative stress[3]
An increase of the intracellular levels of reactive oxygen species (ROS) interferes with the stability of the Keap1–Nrf[2] complex – situated in the cytoplasm – by oxidation of cysteine residues located in a specific domain of
Disruption of the stability of the Keap1–Nrf[2] complex triggers the release of Nrf[2], allowing this protein to reach the nucleus where it behaves as a transcriptional activator of genes that contain the enhancer sequence antioxidant response element (ARE)[5]
Summary
The interaction between Kelch-like ECH-associated protein 1 (Keap1)[1] and the Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2)[2] plays a crucial role in the homeostasis of cellular oxidative stress[3]. The first non-peptide small molecules disrupting the Keap1–Nrf[2] interaction by binding to Keap[1] with micromolar affinities were reported by Hu et al.[10] and Marcotte et al.[11] using high throughput screening methods. Given the commonly ascertained utility of indole as a scaffold for drug-like molecules (see compound 4 in Chart 1), we tried to identify novel indole derivatives which could act as inhibitors of the Keap1–Nrf[2] interaction with the help of molecular modelling and substructure search methods. A few indole-bearing models were superimposed on available 3D structures of inhibitors of the Keap1–Nrf[2] interaction co-crystallised with Keap[1].
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