| Autor: |
Rudovich AS; Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Kuprevich Str., 5/2, 220141 Minsk, Belarus., Peřina M; Department of Experimental Biology, Faculty of Science, Palacký University Olomouc, Šlechtitelů 27, 78371 Olomouc, Czech Republic., Krech AV; Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Kuprevich Str., 5/2, 220141 Minsk, Belarus., Novozhilova MY; Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Kuprevich Str., 5/2, 220141 Minsk, Belarus., Tumilovich AM; Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Kuprevich Str., 5/2, 220141 Minsk, Belarus., Shkel TV; Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Kuprevich Str., 5/2, 220141 Minsk, Belarus., Grabovec IP; Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Kuprevich Str., 5/2, 220141 Minsk, Belarus., Kvasnica M; Department of Experimental Biology, Faculty of Science, Palacký University Olomouc, Šlechtitelů 27, 78371 Olomouc, Czech Republic., Mada L; Department of Experimental Biology, Faculty of Science, Palacký University Olomouc, Šlechtitelů 27, 78371 Olomouc, Czech Republic., Zavialova MG; Institute of Biomedical Chemistry, 10 Building 8, Pogodinskaya Str., 119121 Moscow, Russia., Mekhtiev AR; Institute of Biomedical Chemistry, 10 Building 8, Pogodinskaya Str., 119121 Moscow, Russia., Jorda R; Department of Experimental Biology, Faculty of Science, Palacký University Olomouc, Šlechtitelů 27, 78371 Olomouc, Czech Republic.; Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University Olomouc, Hněvotínská 5, 77900 Olomouc, Czech Republic., Zhabinskii VN; Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Kuprevich Str., 5/2, 220141 Minsk, Belarus., Khripach VA; Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Kuprevich Str., 5/2, 220141 Minsk, Belarus. |
| Abstrakt: |
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 (17 R )-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. |
