Structure activity relationship studies on cytotoxicity and the effects on steroid receptors of AB-functionalized cholestanes

Novel cholestane derivatives were tested to determine relationships between their chemical structure and activity on steroid receptor level as well as their antiproliferative activity. [Display omitted] •Structure-activity relationships of AB-functionalized cholestanes were determined.•The interacti...

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Bibliographic Details
Published in:The Journal of steroid biochemistry and molecular biology 2016-05, Vol.159, p.154-169
Main Authors: Rárová, Lucie, Steigerová, Jana, Kvasnica, Miroslav, Bartůněk, Petr, Křížová, Kateřina, Chodounská, Hana, Kolář, Zdeněk, Sedlák, David, Oklestkova, Jana, Strnad, Miroslav
Format: Article
Language:English
Subjects:
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Antiproliferative activity
Apoptosis
Cell cycle
Cell Cycle - drug effects
Cell Line, Tumor
Cell Survival
Cholestane derivatives
Cholestanes - chemistry
Cholestanes - pharmacology
Drug Screening Assays, Antitumor
Humans
Inhibitory Concentration 50
Receptors, Steroid - metabolism
Steroid receptor
Structure-Activity Relationship
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Summary:Novel cholestane derivatives were tested to determine relationships between their chemical structure and activity on steroid receptor level as well as their antiproliferative activity. [Display omitted] •Structure-activity relationships of AB-functionalized cholestanes were determined.•The interaction with steroid hormone receptors was observed.•Derivatives influenced cell proliferation, cell cycle distribution and apoptosis.•A six-membered B ring is needed for the highest cytotoxicity. Structure-activity relationship analysis and profiling of a library of AB-functionalized cholestane derivatives closely related to brassinosteroids (BRs) were performed to examine their antiproliferative activities and activities on steroid hormone receptors. Some of the compounds were found to have strong cytotoxic activity in several human normal and cancer cell lines. The presence of a 3-hydroxy or 3-oxo group and 2,3-vicinal diol or 3,4-vicinal diol moiety were found to be necessary for optimum biological activity, as well as a six-membered B ring. According to the profiling of all steroid receptors in both agonist and antagonist mode, the majority of the cholestanes were weakly active or inactive compared to the natural ligands. Estrogenic activity was detected for two compounds, two compounds possessed antagonistic properties on estrogen receptors and seven compounds showed agonistic activity. Two active cholestane derivatives were shown to strongly influence cell viability, proliferation, cell cycle distribution, apoptosis and molecular pathways responsible for these processes in hormone-sensitive/insensitive (MCF7/MDA-MB-468) breast cancer cell lines.
ISSN:0960-0760
1879-1220
DOI:10.1016/j.jsbmb.2016.03.017