Abstract
Three new 6-methyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde-thiosemicarbazones-N-4-substituted pro-ligands and their Cu(II) complexes (1, -NH2; 2, -NHMe; 3, -NHEt) have been prepared and characterized. In both the X-ray structures of 1 and 3, two crystallographically independent complex molecules were found that differ either in the nature of weakly metal-binding species (water in 1a and nitrate in 1b) or in the co-ligand (water in 3a and methanol in 3b). Electron Paramagnetic Resonance (EPR) measurements carried out on complexes 1 and 3 confirmed the presence of such different species in the solution. The electrochemical behavior of the pro-ligands and of the complexes was investigated, as well as their biological activity. Complexes 2 and 3 exhibited a high cytotoxicity against human tumor cells and 3D spheroids derived from solid tumors, related to the high cellular uptake. Complexes 2 and 3 also showed a high selectivity towards cancerous cell lines with respect to non-cancerous cell lines and were able to circumvent cisplatin resistance. Via the Transmission Electron Microscopy (TEM) imaging technique, preliminary insights into the biological activity of copper complexes were obtained.
Highlights
IntroductionMolecules 2020, 25, 1868; doi:10.3390/molecules25081868 www.mdpi.com/journal/molecules (TSC) of the type X-C(Z)=N-NH-C(=S)Y, where different combinations of X, Y and Z moieties have been introduced in the framework
Great interest has been reserved in the last decades to the chemistry of thiosemicarbazones (TSC) of the type X-C(Z)=N-NH-C(=S)Y, where different combinations of X, Y and Z moieties haveMolecules 2020, 25, 1868; doi:10.3390/molecules25081868 www.mdpi.com/journal/molecules (TSC) of the type X-C(Z)=N-NH-C(=S)Y, where different combinations of X, Y and Z moieties have been introduced in the framework
Fluorouracil), a suitable o/w partition coefficient to ensure the passive diffusion of the compound through the cell membrane [123], and additional hydrophobic moieties able to be involved in π-π interactions with biomolecules modifying the biological activity
Summary
Molecules 2020, 25, 1868; doi:10.3390/molecules25081868 www.mdpi.com/journal/molecules (TSC) of the type X-C(Z)=N-NH-C(=S)Y, where different combinations of X, Y and Z moieties have been introduced in the framework. This allows for the modulation of the lipophilic properties, been introduced the framework. AttainAan overall desired biological activity as(Chart such 1): or complexes wide range synergistic of medicinaleffect effectsfor of their thiosemicarbazones are well known that of their metal complexes [1,2,3,4,5,6,7,8,9,10,11,12]. 3-TSC (Marboran, no Alonger produced as a drug) as ofbeing antiviral [13], are well known (Chart 1): 1-methylisatin 3-TSC [14,15]). For the modulation the lipophilic properties, chelating abilities in and steric hindrance,This allows by the presence of additionaloffunctional groups, in order chelating and steric effect hindrance, by the presence of additional groups, to attain anabilities overall synergistic for their desired biological activity as such orfunctional that of their metal in order to[1,2,3,4,5,6,7,8,9,10,11,12].
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