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Möller, G. ; Temml, V.* ; Cala Peralta, A.* ; Gruet, O.* ; Richomme, P.* ; Séraphin, D.* ; Viault, G.* ; Kraus, L.* ; Huber-Cantonati, P.* ; Schopfhauser, E.* ; Pachmayr, J.* ; Tokarz, J. ; Schuster, D.* ; Helesbeux, J.J.* ; Dyar, K.A.

Analogues of natural chalcones as efficient inhibitors of AKR1C3.

Metabolites 12:99 (2022)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter 17β-hydroxysteroid Dehydrogenase ; 3α-hydroxysteroid Dehydrogenase ; Akr1c3 ; Aldo-keto Reductase ; Cancer ; Chalcone ; Structure-activity Relationship; Aldo-keto Reductases; Prostaglandin-f Synthase; 5 17-beta-hydroxysteroid-dehydrogenase; Conformer Generation; Crystal-structures; Steroid-hormone; Reveals Roles; 1c3; Type-5; Enzyme
ISSN (print) / ISBN 2218-1989
e-ISSN 2218-1989
Zeitschrift Metabolites
Quellenangaben Band: 12, Heft: 2, Seiten: , Artikelnummer: 99 Supplement: ,
Verlag MDPI
Verlagsort St Alban-anlage 66, Ch-4052 Basel, Switzerland
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Diabetes and Cancer (IDC)
Förderungen Austrian Science Fund (FWF)
RFI Objectif Vegetal (Region Pays de la Loire, France) and the European Regional Development Fund (FEDER)