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...

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Published in:Scientific reports 2022-12, Vol.12 (1), p.20858-20858, Article 20858
Main Authors: Lin, Aye Chan Khine, Netcharoensirisuk, Ponsawan, Sanachai, Kamonpan, Sukma, Warongrit, Chansriniyom, Chaisak, Chaotham, Chatchai, De-Eknamkul, Wanchai, Rungrotmongkol, Thanyada, Chamni, Supakarn
Format: Article
Language:English
Subjects:
631/154
631/154/309
Acids
Alopecia
Amides
Caffeic acid
Cytotoxicity
Dutasteride
Finasteride
Humanities and Social Sciences
Humans
Hydrogen bonding
Keratinocytes
Kinetics
Molecular Docking Simulation
Molecular Dynamics Simulation
multidisciplinary
Science
Science (multidisciplinary)
Steroids
Thin layer chromatography
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Summary: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.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-022-25335-7