Effects of Terminal Substitution and Iron Coordination on Antiproliferative Activity of l-Proline-salicylaldehyde–Thiosemicarbazone Hybrids

A series of five iron(III) complexes, namely [Fe(HL¹)Cl₂] (1), [Fe(HL²)Cl₂]·1.6H₂O (2·1.6H₂O), [Fe(HL³)(MeOH)Cl₂]·0.5H₂O (3·0.5H₂O), [Fe(HL⁴)(MeOH)Cl₂]·0.5H₂O (4·0.5H₂O) and [Fe(HL⁴)(DMF)Cl₂]·0.5Et₂O·H₂O (4′·0.5Et₂O·H₂O), where H₂L¹ = l‐proline‐salicylaldehyde–thiosemicarbazone (l‐Pro‐STSC), H₂L² = pyrrolidine‐substituted l‐Pro‐STSC, H₂L³ = phenyl‐substituted l‐Pro‐STSC, and H₂L⁴ = naphthyl‐substituted l‐Pro‐STSC, have been synthesized. The two ligand precursors (H₂L³ and H₂L⁴) and iron complexes were characterized by elemental analysis, spectroscopic methods (UV/Vis, IR, and NMR), ESI mass spectrometry, cyclic voltammetry, and single‐crystal X‐ray crystallography (1–3 and 4′). Magnetic properties of the five‐coordinate complex 2 and six‐coordinate complex 4 have also been investigated. The antiproliferative activity of the organic hybrids and their iron(III) complexes have been studied in vitro in five human cell lines and one murine cancer cell line, namely HeLa (cervical cancer), FemX (melanoma), A549 (alveolar basal adenocarcinoma), LS‐174 (colon cancer), MDA‐MB‐453 (breast cancer) and MS1 (transformed murine endothelial), as well as in human noncancerous fetal lung fibroblast cell line (MRC‐5). According to the structure–activity relationship, introduction of aromatic groups such as phenyl or naphthyl enhances the cytotoxic potency of the hybrids in the following order H₂L¹ < H₂L² < H₂L³ < H₂L⁴. Coordination of the hybrids to iron(III) improves their antiproliferative activity in the majority of investigated cell lines with exception of H₂L³ in LS‐174, H₂L⁴ in MS1, and both H₂L³ and H₂L⁴ in FemX cell lines, where an opposite effect was observed.