New Water-Soluble Copper(II) Complexes with Morpholine-Thiosemicarbazone Hybrids: Insights into the Anticancer and Antibacterial Mode of Action.
Kateryna OhuiEleonora AfanasenkoFelix BacherRachel Lim Xue TingAyesha ZafarNúria Blanco-CabraEduard TorrentsOrsolya DömötörNóra Veronika MayDenisa DarvasiovaÉva A EnyedyAna Popovic-BijelicJóhannes ReynissonPeter RaptaMaria V BabakGiorgia PastorinVladimir B ArionPublished in: Journal of medicinal chemistry (2018)
Six morpholine-(iso)thiosemicarbazone hybrids HL1-HL6 and their Cu(II) complexes with good-to-moderate solubility and stability in water were synthesized and characterized. Cu(II) complexes [Cu(L1-6)Cl] (1-6) formed weak dimeric associates in the solid state, which did not remain intact in solution as evidenced by ESI-MS. The lead proligands and Cu(II) complexes displayed higher antiproliferative activity in cancer cells than triapine. In addition, complexes 2-5 were found to specifically inhibit the growth of Gram-positive bacteria Staphylococcus aureus with MIC50 values at 2-5 μg/mL. Insights into the processes controlling intracellular accumulation and mechanism of action were investigated for 2 and 5, including the role of ribonucleotide reductase (RNR) inhibition, endoplasmic reticulum stress induction, and regulation of other cancer signaling pathways. Their ability to moderately inhibit R2 RNR protein in the presence of dithiothreitol is likely related to Fe chelating properties of the proligands liberated upon reduction.
Keyphrases
- endoplasmic reticulum stress
- solid state
- water soluble
- staphylococcus aureus
- aqueous solution
- ms ms
- metal organic framework
- induced apoptosis
- signaling pathway
- mass spectrometry
- squamous cell carcinoma
- multiple sclerosis
- small molecule
- squamous cell
- escherichia coli
- reactive oxygen species
- pi k akt
- silver nanoparticles
- gram negative
- drug induced