Synthesis and Biological Evaluation of New Isoxazolyl Steroids as Anti-Prostate Cancer Agents

Synthesis and Biological Evaluation of New Isoxazolyl Steroids as Anti-Prostate Cancer Agents

Steroids with a nitrogen-containing heterocycle in the side chain are known as effective inhibitors of androgen signaling and/or testosterone biosynthesis, thus showing beneficial effects for the treatment of prostate cancer. In this work, a series of 3β-hydroxy-5-ene steroids, containing an isoxazo...

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Bibliographic Details
Published in:International journal of molecular sciences Vol. 23; no. 21; p. 13534
Main Authors: Rudovich, Anton S., Peřina, Miroslav, Krech, Anastasiya V., Novozhilova, Maria Y., Tumilovich, Anastasia M., Shkel, Tatyana V., Grabovec, Irina P., Kvasnica, Miroslav, Mada, Lukáš, Zavialova, Maria G., Mekhtiev, Arif R., Jorda, Radek, Zhabinskii, Vladimir N., Khripach, Vladimir A.
Format: Journal Article
Language:English
Published: Basel MDPI AG 01-11-2022
MDPI
Subjects:
androgen receptor
Androgen receptors
androgen signaling
Androgens
Biological activity
Biosynthesis
Cancer therapies
Chains
CYP17A1
Enzymes
Hydroxylamine
Hydroxylase
isoxazoles
Ketones
Lithium
Molecular docking
Prostate cancer
Steroid hormones
Steroids
Testosterone
Tumor cell lines
Weinreb amide
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Summary:Steroids with a nitrogen-containing heterocycle in the side chain are known as effective inhibitors of androgen signaling and/or testosterone biosynthesis, thus showing beneficial effects for the treatment of prostate cancer. In this work, a series of 3β-hydroxy-5-ene steroids, containing an isoxazole fragment in their side chain, was synthesized. The key steps included the preparation of Weinreb amide, its conversion to acetylenic ketones, and the 1,2- or 1,4-addition of hydroxylamine, depending on the solvent used. The biological activity of the obtained compounds was studied in a number of tests, including their effects on 17α-hydroxylase and 17,20-lyase activity of human CYP17A1 and the ability of selected compounds to affect the downstream androgen receptor signaling. Three derivatives diminished the transcriptional activity of androgen receptor and displayed reasonable antiproliferative activity. The candidate compound, 24j (17R)-17-((3-(2-hydroxypropan-2-yl)isoxazol-5-yl)methyl)-androst-5-en-3β-ol, suppressed the androgen receptor signaling and decreased its protein level in two prostate cancer cell lines, LNCaP and LAPC-4. Interaction of compounds with CYP17A1 and the androgen receptor was confirmed and described by molecular docking.
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ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms232113534