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.

CZ OPENSCREEN National Infrastructure for Chemical Biology Institute of Molecular Genetics AS CR Prague CZ 142 20 Prague Czech Republic

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

Institute of Molecular and Translational Medicine Faculty of Medicine and Dentistry Palacky University and University Hospital in Olomouc CZ 775 15 Olomouc Czech Republic

Institute of Organic Chemistry and Biochemistry AS CR Prague CZ 166 10 Prague Czech Republic

University of Chemistry and Technology Prague Faculty of Food and Biochemical Technology CZ 166 28 Prague Czech Republic

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