Analogues of Natural Chalcones as Efficient Inhibitors of AKR1C3.

Autor:	Möller G; Institute for Diabetes and Cancer, Helmholtz Center Munich, German Research Center for Environmental Health, 85764 Neuherberg, Germany., Temml V; Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Paracelsus Medical University Salzburg, 5020 Salzburg, Austria., Cala Peralta A; University of Angers, SONAS, SFR QUASAV, F-49000 Angers, France., Gruet O; University of Angers, SONAS, SFR QUASAV, F-49000 Angers, France., Richomme P; University of Angers, SONAS, SFR QUASAV, F-49000 Angers, France., Séraphin D; University of Angers, SONAS, SFR QUASAV, F-49000 Angers, France., Viault G; University of Angers, SONAS, SFR QUASAV, F-49000 Angers, France., Kraus L; Institute of Pharmacy, Pharmaceutical Biology and Clinical Pharmacy, Paracelsus Medical University Salzburg, 5020 Salzburg, Austria., Huber-Cantonati P; Institute of Pharmacy, Pharmaceutical Biology and Clinical Pharmacy, Paracelsus Medical University Salzburg, 5020 Salzburg, Austria., Schopfhauser E; Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Paracelsus Medical University Salzburg, 5020 Salzburg, Austria., Pachmayr J; Institute of Pharmacy, Pharmaceutical Biology and Clinical Pharmacy, Paracelsus Medical University Salzburg, 5020 Salzburg, Austria., Tokarz J; Institute for Diabetes and Cancer, Helmholtz Center Munich, German Research Center for Environmental Health, 85764 Neuherberg, Germany., Schuster D; Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Paracelsus Medical University Salzburg, 5020 Salzburg, Austria., Helesbeux JJ; University of Angers, SONAS, SFR QUASAV, F-49000 Angers, France., Dyar KA; Institute for Diabetes and Cancer, Helmholtz Center Munich, German Research Center for Environmental Health, 85764 Neuherberg, Germany.
Jazyk:	angličtina
Zdroj:	Metabolites [Metabolites] 2022 Jan 21; Vol. 12 (2). Date of Electronic Publication: 2022 Jan 21.
DOI:	10.3390/metabo12020099
Abstrakt:	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.
Databáze:	MEDLINE
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