Analogues of Natural Chalcones as Efficient Inhibitors of AKR1C3
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 th...
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MDPI AG
2022-01-01
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| Online Access: | https://www.mdpi.com/2218-1989/12/2/99 |
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| author | Gabriele Möller Veronika Temml Antonio Cala Peralta Océane Gruet Pascal Richomme Denis Séraphin Guillaume Viault Luisa Kraus Petra Huber-Cantonati Elisabeth Schopfhauser Johanna Pachmayr Janina Tokarz Daniela Schuster Jean-Jacques Helesbeux Kenneth Allen Dyar |
| author_facet | Gabriele Möller Veronika Temml Antonio Cala Peralta Océane Gruet Pascal Richomme Denis Séraphin Guillaume Viault Luisa Kraus Petra Huber-Cantonati Elisabeth Schopfhauser Johanna Pachmayr Janina Tokarz Daniela Schuster Jean-Jacques Helesbeux Kenneth Allen Dyar |
| author_sort | Gabriele Möller |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T21:27:18Z |
| format | Article |
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| issn | 2218-1989 |
| language | English |
| last_indexed | 2024-03-09T21:27:18Z |
| publishDate | 2022-01-01 |
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| record_format | Article |
| series | Metabolites |
| spelling | doaj.art-2ab68851bb2c41d1830b279e836dcadf2023-11-23T21:04:24ZengMDPI AGMetabolites2218-19892022-01-011229910.3390/metabo12020099Analogues of Natural Chalcones as Efficient Inhibitors of AKR1C3Gabriele Möller0Veronika Temml1Antonio Cala Peralta2Océane Gruet3Pascal Richomme4Denis Séraphin5Guillaume Viault6Luisa Kraus7Petra Huber-Cantonati8Elisabeth Schopfhauser9Johanna Pachmayr10Janina Tokarz11Daniela Schuster12Jean-Jacques Helesbeux13Kenneth Allen Dyar14Institute for Diabetes and Cancer, Helmholtz Center Munich, German Research Center for Environmental Health, 85764 Neuherberg, GermanyDepartment of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Paracelsus Medical University Salzburg, 5020 Salzburg, AustriaUniversity of Angers, SONAS, SFR QUASAV, F-49000 Angers, FranceUniversity of Angers, SONAS, SFR QUASAV, F-49000 Angers, FranceUniversity of Angers, SONAS, SFR QUASAV, F-49000 Angers, FranceUniversity of Angers, SONAS, SFR QUASAV, F-49000 Angers, FranceUniversity of Angers, SONAS, SFR QUASAV, F-49000 Angers, FranceInstitute of Pharmacy, Pharmaceutical Biology and Clinical Pharmacy, Paracelsus Medical University Salzburg, 5020 Salzburg, AustriaInstitute of Pharmacy, Pharmaceutical Biology and Clinical Pharmacy, Paracelsus Medical University Salzburg, 5020 Salzburg, AustriaDepartment of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Paracelsus Medical University Salzburg, 5020 Salzburg, AustriaInstitute of Pharmacy, Pharmaceutical Biology and Clinical Pharmacy, Paracelsus Medical University Salzburg, 5020 Salzburg, AustriaInstitute for Diabetes and Cancer, Helmholtz Center Munich, German Research Center for Environmental Health, 85764 Neuherberg, GermanyDepartment of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Paracelsus Medical University Salzburg, 5020 Salzburg, AustriaUniversity of Angers, SONAS, SFR QUASAV, F-49000 Angers, FranceInstitute for Diabetes and Cancer, Helmholtz Center Munich, German Research Center for Environmental Health, 85764 Neuherberg, GermanyNaturally 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.https://www.mdpi.com/2218-1989/12/2/99chalconealdo-keto reductasecancerAKR1C317β-hydroxysteroid dehydrogenase3α-hydroxysteroid dehydrogenase |
| spellingShingle | Gabriele Möller Veronika Temml Antonio Cala Peralta Océane Gruet Pascal Richomme Denis Séraphin Guillaume Viault Luisa Kraus Petra Huber-Cantonati Elisabeth Schopfhauser Johanna Pachmayr Janina Tokarz Daniela Schuster Jean-Jacques Helesbeux Kenneth Allen Dyar Analogues of Natural Chalcones as Efficient Inhibitors of AKR1C3 Metabolites chalcone aldo-keto reductase cancer AKR1C3 17β-hydroxysteroid dehydrogenase 3α-hydroxysteroid dehydrogenase |
| title | Analogues of Natural Chalcones as Efficient Inhibitors of AKR1C3 |
| title_full | Analogues of Natural Chalcones as Efficient Inhibitors of AKR1C3 |
| title_fullStr | Analogues of Natural Chalcones as Efficient Inhibitors of AKR1C3 |
| title_full_unstemmed | Analogues of Natural Chalcones as Efficient Inhibitors of AKR1C3 |
| title_short | Analogues of Natural Chalcones as Efficient Inhibitors of AKR1C3 |
| title_sort | analogues of natural chalcones as efficient inhibitors of akr1c3 |
| topic | chalcone aldo-keto reductase cancer AKR1C3 17β-hydroxysteroid dehydrogenase 3α-hydroxysteroid dehydrogenase |
| url | https://www.mdpi.com/2218-1989/12/2/99 |
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