Design, synthesis, and biological evaluation of novel androst-17β-amide structurally related compounds as dual 5α-reductase inhibitors and androgen receptor antagonists

Kejing Lao; Guoliang Xun; Xingchun Gou; Hua Xiang

doi:10.1080/14756366.2019.1654469

Design, synthesis, and biological evaluation of novel androst-17β-amide structurally related compounds as dual 5α-reductase inhibitors and androgen receptor antagonists

J Enzyme Inhib Med Chem. 2019 Dec;34(1):1597-1606. doi: 10.1080/14756366.2019.1654469.

Authors

Kejing Lao^{1

2

3}, Guoliang Xun⁴, Xingchun Gou¹, Hua Xiang^{2

3}

Affiliations

¹ Institute of Basic and Translational Medicine, Shaanxi Key Laboratory of Brain Disorders, Xi'an Medical University , Xi'an , PR China.
² Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University , Nanjing , PR China.
³ Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University , Nanjing , PR China.
⁴ Abbisko Therapeutics Co Ltd , Shanghai , PR China.

Abstract

Prostate cancer (PCa) is the second leading cause of death in men. Apart from androgen receptor, 5α-reductase has also been recognized as a potential target. In this study, a series of androst-17β-amide compounds have been designed and synthesized targeting both AR and 5α-reductase. Their anti-proliferation activities were evaluated in AR + cell line 22RV1 and AR - cell line PC-3. The results indicated that most of the synthesized compounds inhibited the testosterone-stimulated cell proliferation with good selectivity and safety. Among all the compounds, androst[3,2-c]pyrazole derivatives (9a-9d) displayed the best inhibition activity comparable with flutamide. Moreover, most of the synthesized compounds displayed good 5α-reductase inhibitory activities with IC₅₀ lower than 1 μM. The docking result of 9d-AR indicated that AR was forced to expands its binding cavity and maintain an antagonistic conformation since the steric hindrance of 9d impeded H12 transposition. Overall, compound 9d can be identified as a potential dual 5α-reductase inhibitor and AR antagonist, which might be of therapeutic importance for PCa treatment.

Keywords: 5α-reductase Inhibitors; androgen receptor antagonists; prostate cancer.

MeSH terms

5-alpha Reductase Inhibitors / chemical synthesis
5-alpha Reductase Inhibitors / chemistry
5-alpha Reductase Inhibitors / pharmacology*
Androgen Receptor Antagonists / chemical synthesis
Androgen Receptor Antagonists / chemistry
Androgen Receptor Antagonists / pharmacology*
Androstanes / chemical synthesis
Androstanes / chemistry
Androstanes / pharmacology*
Androstenes / chemical synthesis
Androstenes / chemistry
Androstenes / pharmacology*
Cell Proliferation / drug effects
Cell Survival / drug effects
Cholestenone 5 alpha-Reductase / metabolism*
Dose-Response Relationship, Drug
Drug Design*
Humans
Models, Molecular
Molecular Structure
PC-3 Cells
Receptors, Androgen / metabolism*
Structure-Activity Relationship
Tumor Cells, Cultured

Substances

5-alpha Reductase Inhibitors
AR protein, human
Androgen Receptor Antagonists
Androstanes
Androstenes
Receptors, Androgen
androst-17beta-amide
Cholestenone 5 alpha-Reductase

Grants and funding

This work was supported by grants from the Research Fund of Shaanxi Provincial Education Department [grant number 18JS104] and Natural Science Basic Research Plan in Shaanxi Province of China [grant number 2019JQ-202]. We thank the support of The Youth Innovation Team of Shaanxi Universities.