Investigation of the cytotoxic potential of imidazole-derived thiosemicarbazones and their copper( ii ) complexes with CHCl ₂ CO ₂ ⁻ as a co-ligand.

A series of four water-soluble salicylaldehyde thiosemicarbazones with a positively charged trimethylammonium moiety ([H₂L^R]Cl, R = H, Me, Et, Ph) and four copper(II) complexes [Cu(HL^R)Cl]Cl (1–4) were synthesised with the aim to study (i) their antiproliferative activity in cancer cells and, (ii) for the first time for thiosemicarbazones, the interaction with membrane transport proteins, specifically organic cation transporters OCT1–3. The compounds were comprehensively characterised by analytical, spectroscopic and X-ray diffraction methods. The highest cytotoxic effect was observed in the neuroblastoma cell line SH-5YSY after 24 h exposure and follows the rank order: 3 > 2 > 4 > cisplatin > 1 >> [H₂L^R]Cl. The copper(II) complexes showed marked interaction with OCT1–3, comparable to that of well-known OCT inhibitors (decynium 22, prazosin and corticosterone) in the cell-based radiotracer uptake assays. The work paves the way for the development of more potent and selective anticancer drugs and/or OCT inhibitors.

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.

The metal-to-ligand stoichiometry and metal identity are of primary importance for the development of metal complexes of thiosemicarbazones as effective inhibitors of tubulin polymerization.