New Water-Soluble Copper(II) Complexes with Morpholine–Thiosemicarbazone Hybrids: Insights into the Anticancer and Antibacterial Mode of Action

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.