Substituted Aryl Benzylamines as Potent and Selective Inhibitors of 17β-Hydroxysteroid Dehydrogenase Type 3.
Authors
Vicker, Nigel
Bailey, Helen V
Day, Joanna M
Mahon, Mary F
Smith, Andrew
Purohit, Atul
Publication Date
2021-11-26Journal Title
Molecules
ISSN
1420-3049
Publisher
MDPI AG
Volume
26
Issue
23
Language
en
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Vicker, N., Bailey, H. V., Day, J. M., Mahon, M. F., Smith, A., Tutill, H. J., Purohit, A., & et al. (2021). Substituted Aryl Benzylamines as Potent and Selective Inhibitors of 17β-Hydroxysteroid Dehydrogenase Type 3.. Molecules, 26 (23) https://doi.org/10.3390/molecules26237166
Abstract
17β-Hydroxysteroid dehydrogenase type 3 (17β-HSD3) is expressed at high levels in testes and seminal vesicles; it is also present in prostate tissue and involved in gonadal and non-gonadal testosterone biosynthesis. The enzyme is membrane-bound, and a crystal structure is not yet available. Selective aryl benzylamine-based inhibitors were designed and synthesised as potential agents for prostate cancer therapeutics through structure-based design, using a previously built homology model with docking studies. Potent, selective, low nanomolar IC50 17β-HSD3 inhibitors were discovered using N-(2-([2-(4-chlorophenoxy)phenylamino]methyl)phenyl)acetamide (1). The most potent compounds have IC50 values of approximately 75 nM. Compound 29, N-[2-(1-Acetylpiperidin-4-ylamino)benzyl]-N-[2-(4-chlorophenoxy)phenyl]acetamide, has an IC50 of 76 nM, while compound 30, N-(2-(1-[2-(4-chlorophenoxy)-phenylamino]ethyl)phenyl)acetamide, has an IC50 of 74 nM. Racemic C-allyl derivative 26 (IC50 of 520 nM) was easily formed from 1 in good yield and, to determine binding directionality, its enantiomers were separated by chiral chromatography. Absolute configuration was determined using single crystal X-ray crystallography. Only the S-(+)-enantiomer (32) was active with an IC50 of 370 nM. Binding directionality was predictable through our in silico docking studies, giving confidence to our model. Importantly, all novel inhibitors are selective over the type 2 isozyme of 17β-HSD2 and show <20% inhibition when tested at 10 µM. Lead compounds from this series are worthy of further optimisation and development as inhibitors of testosterone production by 17β-HSD3 and as inhibitors of prostate cancer cell growth.
Keywords
X-ray crystallography, chiral chromatography, dehydrogenase, homology modelling, prostate cancer, synthesis, 17-Hydroxysteroid Dehydrogenases, Benzylamines, Cell Line, Tumor, Crystallography, X-Ray, Enzyme Inhibitors, Humans, Inhibitory Concentration 50, Male, Molecular Docking Simulation, Prostate, Prostatic Neoplasms, Structure-Activity Relationship, Testosterone
Sponsorship
Sterix Ltd (N/A)
Identifiers
External DOI: https://doi.org/10.3390/molecules26237166
This record's URL: https://www.repository.cam.ac.uk/handle/1810/331470
Rights
Licence:
https://creativecommons.org/licenses/by/4.0/
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