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Trilobolide-steroid hybrids: Synthesis, cytotoxic and antimycobacterial activity
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SYSNO ASEP 0473082 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Trilobolide-steroid hybrids: Synthesis, cytotoxic and antimycobacterial activity Author(s) Jurášek, M. (CZ)
Džubák, P. (CZ)
Rimpelová, S. (CZ)
Sedlák, David (UMG-J) RID
Konečný, P. (CZ)
Frydrych, I. (CZ)
Gurska, S. (CZ)
Hajdúch, M. (CZ)
Bogdanová, K. (CZ)
Kolář, M. (CZ)
Muller, Tomáš (UMG-J)
Kmoníčková, Eva (UEM-P) RID
Ruml, T. (CZ)
Harmatha, Juraj (UOCHB-X) RID, ORCID
Drašar, P. B. (CZ)Number of authors 15 Source Title Steroids. - : Elsevier - ISSN 0039-128X
Roč. 117, JAN (2017), s. 97-104Number of pages 8 s. Language eng - English Country US - United States Keywords Trilobolide ; Steroids ; Click chemistry ; Cytotoxicity ; sar ; Steroid receptor Subject RIV EB - Genetics ; Molecular Biology OECD category Biochemistry and molecular biology Subject RIV - cooperation Institute of Organic Chemistry and Biochemistry - Organic Chemistry R&D Projects LO1304 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) LO1220 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) LM2015063 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Institutional support UMG-J - RVO:68378050 ; UEM-P - RVO:68378041 ; UOCHB-X - RVO:61388963 UT WOS 000392566800014 DOI https://doi.org/10.1016/j.steroids.2016.08.011 Annotation Sesquiterpene lactone trilobolide is a sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) inhibitor, thus depleting the Ins(1,4,5)P3-sensitive intracellular calcium stores. Here, we describe a synthesis of a series of 6 trilobolide-steroids conjugates (estradiol, pregnene, dehydroepiandrosterone, and testosterone). We found that the newly synthesized Tb-based compounds possess different remarkable biologital activities. Cancer cell cytotoxicity and preferential selectivity is represented in our study by a Tb-pregnene derivative. The most cytotoxic clickates of estradiol and pregnene were studied by FACS where impact on cell cycle and RNA synthesis was observed; live-cell microscopy revealed the impact on cell organelle morphology particularly endoplasmic reticulum, mitochondria and nucleus. Further, we have studied the estrogenic and androgenic properties of the cliCkate molecules using cell-based luciferase assays. Finally, antimycobacterial tests revealed that testosterone and estradiol derivatives potentiated the antimycobacterial activity up to IC50 of 10.6 mu M. (C) 2016 Elsevier Inc. All rights reserved. Workplace Institute of Molecular Genetics Contact Nikol Škňouřilová, nikol.sknourilova@img.cas.cz, Tel.: 241 063 217 Year of Publishing 2017
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