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J Steroid Biochem Mol Biol. 2016 May;159:154-69. doi: 10.1016/j.jsbmb.2016.03.017. Epub 2016 Mar 11.

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

Author information

1
Department of Chemical Biology and Genetics, Centre of the Region Haná for Biotechnological and Agricultural Research, Palacký University, Šlechtitelů 27, 78371 Olomouc, Czech Republic. Electronic address: lucie.rarova@upol.cz.
2
Laboratory of Molecular Pathology, Institute of Clinical and Molecular Pathology, Faculty of Medicine, Palacký University, Hněvotínská 5, 77900 Olomouc, Czech Republic; Institute of Molecular and Translation Medicine, Faculty of Medicine and Dentistry, Palacký University and Faculty Hospital in Olomouc, Hněvotínská 5, 77900 Olomouc, Czech Republic. Electronic address: jana.steigerova@seznam.cz.
3
Laboratory of Growth Regulators, Centre of the Region Haná for Biotechnological and Agricultural Research, Institute of Experimental Botany ASCR & Palacký University, Šlechtitelů 27, 78371 Olomouc, Czech Republic. Electronic address: mirek.kv@seznam.cz.
4
CZ-OPENSCREEN: National Infrastructure for Chemical Biology, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Vídeňská 1083, 142 20 Praha 4, Czech Republic. Electronic address: petr.bartunek@img.cas.cz.
5
Laboratory of Molecular Pathology, Institute of Clinical and Molecular Pathology, Faculty of Medicine, Palacký University, Hněvotínská 5, 77900 Olomouc, Czech Republic; Institute of Molecular and Translation Medicine, Faculty of Medicine and Dentistry, Palacký University and Faculty Hospital in Olomouc, Hněvotínská 5, 77900 Olomouc, Czech Republic. Electronic address: k.krizova@upol.cz.
6
Institute of Organic Chemistry and Biochemistry of the Academy of Sciences of the Czech Republic, v.v.i, Flemingovo nám. 2, 166 10 Prague 6, Czech Republic. Electronic address: hchod@uochb.cas.cz.
7
Laboratory of Molecular Pathology, Institute of Clinical and Molecular Pathology, Faculty of Medicine, Palacký University, Hněvotínská 5, 77900 Olomouc, Czech Republic. Electronic address: zdenek.kolar@upol.cz.
8
CZ-OPENSCREEN: National Infrastructure for Chemical Biology, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Vídeňská 1083, 142 20 Praha 4, Czech Republic. Electronic address: david.sedlak@img.cas.cz.
9
Laboratory of Growth Regulators, Centre of the Region Haná for Biotechnological and Agricultural Research, Institute of Experimental Botany ASCR & Palacký University, Šlechtitelů 27, 78371 Olomouc, Czech Republic. Electronic address: jana.oklestkova@upol.cz.
10
Laboratory of Growth Regulators, Centre of the Region Haná for Biotechnological and Agricultural Research, Institute of Experimental Botany ASCR & Palacký University, Šlechtitelů 27, 78371 Olomouc, Czech Republic. Electronic address: miroslav.strnad@upol.cz.

Abstract

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.

KEYWORDS:

Antiproliferative activity; Apoptosis; Cell cycle; Cholestane derivatives; Steroid receptor; Structure-activity relationship

PMID:
26976651
DOI:
10.1016/j.jsbmb.2016.03.017
[Indexed for MEDLINE]

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