Trilobolide-steroid hybrids: Synthesis, cytotoxic and antimycobacterial activity

- 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 10.6 μM.

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