title: Trilobolide-steroid hybrids: Synthesis, cytotoxic and antimycobacterial activity.
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.
authors.affiliation: University of Chemistry and Technology Prague, Faculty of Food and Biochemical Technology, CZ-166 28 Prague, Czech Republic.
authors.forename: Michal
authors.initials: M
authors.lastname: Jurášek
authors.affiliation: 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.
authors.forename: Petr
authors.initials: P
authors.lastname: Džubák
authors.affiliation: University of Chemistry and Technology Prague, Faculty of Food and Biochemical Technology, CZ-166 28 Prague, Czech Republic.
authors.forename: Silvie
authors.initials: S
authors.lastname: Rimpelová
authors.affiliation: CZ-OPENSCREEN: National Infrastructure for Chemical Biology, Institute of Molecular Genetics AS CR Prague, CZ-142 20 Prague, Czech Republic.
authors.forename: David
authors.initials: D
authors.lastname: Sedlák
authors.affiliation: Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University and University Hospital in Olomouc, CZ-775 15 Olomouc, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Konečný
authors.affiliation: Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University and University Hospital in Olomouc, CZ-775 15 Olomouc, Czech Republic.
authors.forename: Ivo
authors.initials: I
authors.lastname: Frydrych
authors.affiliation: Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University and University Hospital in Olomouc, CZ-775 15 Olomouc, Czech Republic.
authors.forename: Soňa
authors.initials: S
authors.lastname: Gurská
authors.affiliation: Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University and University Hospital in Olomouc, CZ-775 15 Olomouc, Czech Republic.
authors.forename: Marián
authors.initials: M
authors.lastname: Hajdúch
authors.affiliation: Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University and University Hospital in Olomouc, CZ-775 15 Olomouc, Czech Republic.
authors.forename: Kateřina
authors.initials: K
authors.lastname: Bogdanová
authors.affiliation: Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University and University Hospital in Olomouc, CZ-775 15 Olomouc, Czech Republic.
authors.forename: Milan
authors.initials: M
authors.lastname: Kolář
authors.affiliation: CZ-OPENSCREEN: National Infrastructure for Chemical Biology, Institute of Molecular Genetics AS CR Prague, CZ-142 20 Prague, Czech Republic.
authors.forename: Tomáš
authors.initials: T
authors.lastname: Müller
authors.affiliation: 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.
authors.forename: Eva
authors.initials: E
authors.lastname: Kmoníčková
authors.affiliation: University of Chemistry and Technology Prague, Faculty of Food and Biochemical Technology, CZ-166 28 Prague, Czech Republic.
authors.forename: Tomáš
authors.initials: T
authors.lastname: Ruml
authors.affiliation: Institute of Organic Chemistry and Biochemistry AS CR Prague, CZ-166 10 Prague, Czech Republic.
authors.forename: Juraj
authors.initials: J
authors.lastname: Harmatha
authors.affiliation: University of Chemistry and Technology Prague, Faculty of Food and Biochemical Technology, CZ-166 28 Prague, Czech Republic. Electronic address: pavel.drasar@vscht.cz.
authors.forename: Pavel B
authors.initials: PB
authors.lastname: Drašar
mesh_terms: D000072283:A549 Cells; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002087:Butyrates / Q000737:chemistry*; D002175:Candida / Q000187:drug effects; D045744:Cell Line, Tumor; D057930:Click Chemistry; D005663:Furans / Q000737:chemistry*; D045325:HCT116 Cells; D006801:Humans; D015394:Molecular Structure; D011944:Receptors, Androgen / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011987:Receptors, Steroid / Q000378:metabolism; D013256:Steroids / Q000737:chemistry*
chemical_list: D000900:Anti-Bacterial Agents; D002087:Butyrates; D005663:Furans; D011944:Receptors, Androgen; D011960:Receptors, Estrogen; D011987:Receptors, Steroid; D013256:Steroids; C086352:trilobolide
keywords: Click chemistry; Cytotoxicity; SAR; Steroid receptor; Steroids; Trilobolide