Trilobolide-steroid hybrids: Synthesis, cytotoxic and antimycobacterial activity

• Published in: Steroids 2017-01, Vol.117, p.97-104
• Main Authors: Jurášek, Michal, Džubák, Petr, Rimpelová, Silvie, Sedlák, David, Konečný, Petr, Frydrych, Ivo, Gurská, Soňa, Hajdúch, Marián, Bogdanová, Kateřina, Kolář, Milan, Müller, Tomáš, Kmoníčková, Eva, Ruml, Tomáš, Harmatha, Juraj, Drašar, Pavel B.
• Format: Article
• Language: English
• Subjects: A549 Cells; Animals; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Butyrates - chemistry; Candida - drug effects; Cell Line, Tumor; Click Chemistry; Cytotoxicity; Furans - chemistry; HCT116 Cells; Humans; Molecular Structure; Receptors, Androgen - metabolism; Receptors, Estrogen - metabolism; Receptors, Steroid - metabolism; SAR; Steroid receptor; Steroids; Steroids - chemistry; Trilobolide
• ISSN: 0039-128X; 1878-5867
• DOI: 10.1016/j.steroids.2016.08.011

[Display omitted] •Five trilobolide-steroid hybrids were synthesized using CuAAC approach.•Cytotoxicity was tested on a 12 cancer and 3 non-cancerous cell lines. The most cytotoxic compounds were tested for cell-cycle analysis on CCRF-CEM line.•The potency on androgen (AR) and estrogen (α,β-ER) receptors was examined.•Impact on cell morphology was studied by live-cell microscopy.•Compounds were tested against 8 sensitive and multiresistant bacterial and Candida strains. 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.