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Steroids. 2017 Jan;117:97-104. doi: 10.1016/j.steroids.2016.08.011. Epub 2016 Aug 17.

Trilobolide-steroid hybrids: Synthesis, cytotoxic and antimycobacterial activity.

Author information

1
University of Chemistry and Technology Prague, Faculty of Food and Biochemical Technology, CZ-166 28 Prague, Czech Republic.
2
Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University and University Hospital in Olomouc, CZ-775 15 Olomouc, Czech Republic. Electronic address: dzubakp@gmail.com.
3
CZ-OPENSCREEN: National Infrastructure for Chemical Biology, Institute of Molecular Genetics AS CR Prague, CZ-142 20 Prague, Czech Republic.
4
Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University and University Hospital in Olomouc, CZ-775 15 Olomouc, Czech Republic.
5
Institute of Experimental Medicine, Department of Pharmacology AS CR, Prague, Czech Republic; Institute of Pharmacology and Toxicology and Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Prague, Czech Republic.
6
Institute of Organic Chemistry and Biochemistry AS CR Prague, CZ-166 10 Prague, Czech Republic.
7
University of Chemistry and Technology Prague, Faculty of Food and Biochemical Technology, CZ-166 28 Prague, Czech Republic. Electronic address: pavel.drasar@vscht.cz.

Abstract

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 biological 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 10.6μM.

KEYWORDS:

Click chemistry; Cytotoxicity; SAR; Steroid receptor; Steroids; Trilobolide

PMID:
27543674
DOI:
10.1016/j.steroids.2016.08.011
[Indexed for MEDLINE]

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