Synthesis, structural analysis and antitumor activity of novel 17α-picolyl and 17(E)-picolinylidene A-modified androstane derivatives

[Display omitted] The heterocyclic ring at C-17 position of the androstane compounds plays an important role in biological activity. The aim of the present study was to synthesize and evaluate potential antitumor activity of different A-modified 17α-picolyl and 17(E)-picolinylidene androstane deriva...

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Published in:Bioorganic & medicinal chemistry 2015-04, Vol.23 (7), p.1557-1568
Main Authors: Ajduković, Jovana J., Penov Gaši, Katarina M., Jakimov, Dimitar S., Klisurić, Olivera R., Jovanović-Šanta, Suzana S., Sakač, Marija N., Aleksić, Lidija D., Djurendić, Evgenija A.
Format: Article
Language:English
Subjects:
Androstane derivatives
Androstanes - chemical synthesis
Androstanes - pharmacology
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - pharmacology
Antiproliferative activity
Apoptosis
Apoptosis - drug effects
Cell Line, Tumor
Female
HeLa Cells
HT29 Cells
Humans
MCF-7 Cells
Structure-Activity Relationship
Synthesis
X-ray
X-Ray Diffraction
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Summary:[Display omitted] The heterocyclic ring at C-17 position of the androstane compounds plays an important role in biological activity. The aim of the present study was to synthesize and evaluate potential antitumor activity of different A-modified 17α-picolyl and 17(E)-picolinylidene androstane derivatives. In several synthetic steps, novel derivatives bearing the hydroximino, nitrile or lactame functions in A-ring were synthesized and characterized according to the spectral data, by mass analysis as well as XRD analysis (compounds 6, 13 and 15). The structurally most promising compounds 6, 11–17 were investigated as antitumor agents. The in vitro antiproliferative activity was evaluated against six human cancer cell lines: estrogen receptor negative (ER−) breast adenocarcinoma (MDA-MB-231); estrogen receptor positive (ER+) breast adenocarcinoma (MCF-7); prostate cancer (PC-3); human cervical carcinoma (HeLa); lung adenocarcinoma (A549) and colon adenocarcinoma (HT-29) using MTT assay. The results of the 48h incubation time in vitro tests showed that compound 15 was the most effective against PC-3 (IC50 6.6μM), compound 17 against MCF-7 (IC50 7.9μM) cells, while compound 16 exhibited strong antiproliferative effect against both, MCF-7 (IC50 1.7μM) and PC-3 (IC50 8.7μM) cancer cells. It was also found that compounds 16 and 17 induced apoptosis in MCF-7 cells (dicyano derivative 17 stronger then dioxime 16 and reference formestane), with no distinct changes in the cell cycle of MCF-7 cells.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2015.02.001