Analogues of Natural Chalcones as Efficient Inhibitors of AKR1C3 - Substances d'Origine Naturelle et Analogues Structuraux Accéder directement au contenu
Article Dans Une Revue Metabolites Année : 2022

Analogues of Natural Chalcones as Efficient Inhibitors of AKR1C3

Gabriele Möller
Veronika Temml
  • Fonction : Auteur
Luisa Kraus
  • Fonction : Auteur
Petra Huber-Cantonati
  • Fonction : Auteur
Elisabeth Schopfhauser
  • Fonction : Auteur
Johanna Pachmayr
  • Fonction : Auteur
Janina Tokarz
Daniela Schuster
Kenneth Allen Dyar

Résumé

Naturally occurring substances are valuable resources for drug development. In this respect, chalcones are known to be antiproliferative agents against prostate cancer cell lines through various mechanisms or targets. Based on the literature and preliminary results, we aimed to study and optimise the efficiency of a series of chalcones to inhibit androgen-converting AKR1C3, known to promote prostate cancer. A total of 12 chalcones with different substitution patterns were synthesised. Structure–activity relationships associated with these modifications on AKR1C3 inhibition were analysed by performing enzymatic assays and docking simulations. In addition, the selectivity and cytotoxicity of the compounds were assessed. In enzymatic assays, C-6′ hydroxylated derivatives were more active than C-6′ methoxylated derivatives. In contrast, C-4 methylation increased activity over C-4 hydroxylation. Docking results supported these findings with the most active compounds fitting nicely in the binding site and exhibiting strong interactions with key amino acid residues. The most effective inhibitors were not cytotoxic for HEK293T cells and selective for 17β-hydroxysteroid dehydrogenases not primarily involved in steroid hormone metabolism. Nevertheless, they inhibited several enzymes of the steroid metabolism pathways. Favourable substitutions that enhanced AKR1C3 inhibition of chalcones were identified. This study paves the way to further develop compounds from this series or related flavonoids with improved inhibitory activity against AKR1C3.
Fichier principal
Vignette du fichier
26- G. Moller er al. metabolites 2022, 12, 99.pdf (4.47 Mo) Télécharger le fichier
Origine : Fichiers éditeurs autorisés sur une archive ouverte

Dates et versions

hal-03782968 , version 1 (23-09-2022)

Licence

Paternité

Identifiants

Citer

Gabriele Möller, Veronika Temml, Antonio Cala Peralta, Océane Gruet, Pascal Richomme, et al.. Analogues of Natural Chalcones as Efficient Inhibitors of AKR1C3. Metabolites, 2022, 12 (2), pp.99. ⟨10.3390/metabo12020099⟩. ⟨hal-03782968⟩

Collections

UNIV-ANGERS SONAS
12 Consultations
41 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More