Steroids are often considered valuable molecular tools for the development of anticancer
agents with improved pharmacological properties. Conjugation of metal chelating moieties
with a lipophilic sterane backbone is a viable option to obtain novel anticancer compounds.
In this work, two estradiol-based hybrid molecules (PMA-E2 and DMA-E2) with an (N,N,O)
binding motif and their Cu(II) complexes were developed. The lipophilicity, solubility,
and acid-base properties of the novel ligands were determined by the combined use
of UV-visible spectrophotometry, pH-potentiometry, and 1H NMR spectroscopy. The solution
speciation and redox activity of the Cu(II) complexes were also investigated by means
of UV-visible and electron paramagnetic resonance spectroscopy. Two structurally analogous
ligands (PMAP and DMAP) were also included in the studies for better interpretation
of the solution chemical data obtained. Three pKa values were determined for all ligands,
revealing the order of the deprotonation steps: pyridinium-NH+ or NH(CH3)2+, secondary
NH2+, and OH. The dimethylamine derivatives (DMA-E2, DMAP) are found in their H2L+
forms in solution at pH 7.4, whereas the fraction of the neutral HL species is significant
(34–37%) in the case of the pyridine nitrogen-containing derivatives (PMA-E2, PMAP).
Both estradiol derivatives were moderately cytotoxic in human breast (MCF-7) and colon
adenocarcinoma (Colo-205) cells (IC50 = 30–63 μM). They form highly stable complexes
with Cu(II) ions capable of oxidizing ascorbate and glutathione. These Cu(II) complexes
are somewhat more cytotoxic (IC50 = 15–45 μM) than their corresponding ligands and
show a better selectivity profile.
