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Caffeic acid N-[3,5-bis(trifluoromethyl)phenyl] amide as a non-steroidal inhibitor for steroid 5α-reductase type 1 using a human keratinocyte cell-based assay and molecular dynamics

Caffeic acid derivatives containing amide moieties similar to those of finasteride and dutasteride were synthesized. An in vitro inhibitory activity evaluation of caffeic acid (1) and its amide derivatives (2 − 4) against the steroid 5α-reductase type 1 (SRD5A1) produced by human keratinocyte cells...

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Autores principales: Lin, Aye Chan Khine, Netcharoensirisuk, Ponsawan, Sanachai, Kamonpan, Sukma, Warongrit, Chansriniyom, Chaisak, Chaotham, Chatchai, De-Eknamkul, Wanchai, Rungrotmongkol, Thanyada, Chamni, Supakarn
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9718795/
https://www.ncbi.nlm.nih.gov/pubmed/36460729
http://dx.doi.org/10.1038/s41598-022-25335-7
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author Lin, Aye Chan Khine
Netcharoensirisuk, Ponsawan
Sanachai, Kamonpan
Sukma, Warongrit
Chansriniyom, Chaisak
Chaotham, Chatchai
De-Eknamkul, Wanchai
Rungrotmongkol, Thanyada
Chamni, Supakarn
author_facet Lin, Aye Chan Khine
Netcharoensirisuk, Ponsawan
Sanachai, Kamonpan
Sukma, Warongrit
Chansriniyom, Chaisak
Chaotham, Chatchai
De-Eknamkul, Wanchai
Rungrotmongkol, Thanyada
Chamni, Supakarn
author_sort Lin, Aye Chan Khine
collection PubMed
description Caffeic acid derivatives containing amide moieties similar to those of finasteride and dutasteride were synthesized. An in vitro inhibitory activity evaluation of caffeic acid (1) and its amide derivatives (2 − 4) against the steroid 5α-reductase type 1 (SRD5A1) produced by human keratinocyte cells coupled with the non-radioactive high-performance thin-layer chromatography detection revealed that caffeic acid N-[3,5-bis(trifluoromethyl)phenyl] amide (4) was a promising non-steroidal suppressor, with a half-maximal inhibitory concentration (IC(50)) of 1.44 ± 0.13 µM and relatively low cytotoxicity with an IC(50) of 29.99 ± 8.69 µM. The regulatory role of compound 4 against SRD5A1 involved both suppression of SRD5A1 expression and mixed mode SRD5A1 inhibition. The K(i) value of compound 4 was 2.382 µM based on the whole-cell kinetic studies under specific conditions. Molecular docking and molecular dynamics simulations with AlphaFold generated the human SRD5A1 structure and confirmed the stability of compound 4 at the SRD5A1 catalytic site with greater interactions, including hydrogen bonding of the key M119 amino-acid residue than those of finasteride and dutasteride. Thus, compound 4 shows the potential for further development as an SRD5A1 suppressor for androgenic alopecia treatment.
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spelling pubmed-97187952022-12-04 Caffeic acid N-[3,5-bis(trifluoromethyl)phenyl] amide as a non-steroidal inhibitor for steroid 5α-reductase type 1 using a human keratinocyte cell-based assay and molecular dynamics Lin, Aye Chan Khine Netcharoensirisuk, Ponsawan Sanachai, Kamonpan Sukma, Warongrit Chansriniyom, Chaisak Chaotham, Chatchai De-Eknamkul, Wanchai Rungrotmongkol, Thanyada Chamni, Supakarn Sci Rep Article Caffeic acid derivatives containing amide moieties similar to those of finasteride and dutasteride were synthesized. An in vitro inhibitory activity evaluation of caffeic acid (1) and its amide derivatives (2 − 4) against the steroid 5α-reductase type 1 (SRD5A1) produced by human keratinocyte cells coupled with the non-radioactive high-performance thin-layer chromatography detection revealed that caffeic acid N-[3,5-bis(trifluoromethyl)phenyl] amide (4) was a promising non-steroidal suppressor, with a half-maximal inhibitory concentration (IC(50)) of 1.44 ± 0.13 µM and relatively low cytotoxicity with an IC(50) of 29.99 ± 8.69 µM. The regulatory role of compound 4 against SRD5A1 involved both suppression of SRD5A1 expression and mixed mode SRD5A1 inhibition. The K(i) value of compound 4 was 2.382 µM based on the whole-cell kinetic studies under specific conditions. Molecular docking and molecular dynamics simulations with AlphaFold generated the human SRD5A1 structure and confirmed the stability of compound 4 at the SRD5A1 catalytic site with greater interactions, including hydrogen bonding of the key M119 amino-acid residue than those of finasteride and dutasteride. Thus, compound 4 shows the potential for further development as an SRD5A1 suppressor for androgenic alopecia treatment. Nature Publishing Group UK 2022-12-02 /pmc/articles/PMC9718795/ /pubmed/36460729 http://dx.doi.org/10.1038/s41598-022-25335-7 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Lin, Aye Chan Khine
Netcharoensirisuk, Ponsawan
Sanachai, Kamonpan
Sukma, Warongrit
Chansriniyom, Chaisak
Chaotham, Chatchai
De-Eknamkul, Wanchai
Rungrotmongkol, Thanyada
Chamni, Supakarn
Caffeic acid N-[3,5-bis(trifluoromethyl)phenyl] amide as a non-steroidal inhibitor for steroid 5α-reductase type 1 using a human keratinocyte cell-based assay and molecular dynamics
title Caffeic acid N-[3,5-bis(trifluoromethyl)phenyl] amide as a non-steroidal inhibitor for steroid 5α-reductase type 1 using a human keratinocyte cell-based assay and molecular dynamics
title_full Caffeic acid N-[3,5-bis(trifluoromethyl)phenyl] amide as a non-steroidal inhibitor for steroid 5α-reductase type 1 using a human keratinocyte cell-based assay and molecular dynamics
title_fullStr Caffeic acid N-[3,5-bis(trifluoromethyl)phenyl] amide as a non-steroidal inhibitor for steroid 5α-reductase type 1 using a human keratinocyte cell-based assay and molecular dynamics
title_full_unstemmed Caffeic acid N-[3,5-bis(trifluoromethyl)phenyl] amide as a non-steroidal inhibitor for steroid 5α-reductase type 1 using a human keratinocyte cell-based assay and molecular dynamics
title_short Caffeic acid N-[3,5-bis(trifluoromethyl)phenyl] amide as a non-steroidal inhibitor for steroid 5α-reductase type 1 using a human keratinocyte cell-based assay and molecular dynamics
title_sort caffeic acid n-[3,5-bis(trifluoromethyl)phenyl] amide as a non-steroidal inhibitor for steroid 5α-reductase type 1 using a human keratinocyte cell-based assay and molecular dynamics
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9718795/
https://www.ncbi.nlm.nih.gov/pubmed/36460729
http://dx.doi.org/10.1038/s41598-022-25335-7
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