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

Autor: Anton S. Rudovich, Miroslav Peřina, Anastasiya V. Krech, Maria Y. Novozhilova, Anastasia M. Tumilovich, Tatyana V. Shkel, Irina P. Grabovec, Miroslav Kvasnica, Lukáš Mada, Maria G. Zavialova, Arif R. Mekhtiev, Radek Jorda, Vladimir N. Zhabinskii, Vladimir A. Khripach
Jazyk: angličtina
Rok vydání: 2022
Předmět:
Zdroj: International Journal of Molecular Sciences, Vol 23, Iss 21, p 13534 (2022)
Druh dokumentu: article
ISSN: 1422-0067
1661-6596
DOI: 10.3390/ijms232113534
Popis: 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.
Databáze: Directory of Open Access Journals
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