Trilobolide-steroid hybrids: Synthesis, cytotoxic and antimycobacterial activity

0473082 - ÚMG 2017 RIV US eng J - Journal Article
Jurášek, M. - Džubák, P. - Rimpelová, S. - Sedlák, David - Konečný, P. - Frydrych, I. - Gurska, S. - Hajdúch, M. - Bogdanová, K. - Kolář, M. - Muller, Tomáš - Kmoníčková, Eva - Ruml, T. - Harmatha, Juraj - Drašar, P. B.
Trilobolide-steroid hybrids: Synthesis, cytotoxic and antimycobacterial activity.
Steroids. Roč. 117, JAN (2017), s. 97-104. ISSN 0039-128X. E-ISSN 1878-5867
R&D Projects: GA MŠMT(CZ) LO1304; GA MŠMT LO1220; GA MŠMT LM2015063
Grant - others:GA ČR(CZ) GA14-04329S
Institutional support: RVO:68378050 ; RVO:68378041 ; RVO:61388963
Keywords : Trilobolide * Steroids * Click chemistry * Cytotoxicity * sar * Steroid receptor
OECD category: Biochemistry and molecular biology; Organic chemistry (UOCHB-X)
Impact factor: 2.523, year: 2017

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.
Permanent Link: http://hdl.handle.net/11104/0270248