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.This study was financially supported by the Austrian Science Fund (project number P28223 N34), Research and Development Agency of the Slovak Republic under the contracts No. APVV 15-0079 and APVV-15-0053, Scientific Grant Agency of the Slovak Republic (VEGA Project 1/0871/16) and Slovak University of Technology in Bratislava (Young Researcher Grant, M. Milunović, PhD) This work was also supported by Ministry of Education, Science, Research and Sport of the Slovak Republic withinhe Research and Development Operational Program for the project "University Science Park of STU Bratislava", ITMS 26240220084, cofunded by the European Regional Development Fund

Insight into the Anticancer Activity of Copper(II) 5-Methylenetrimethylammonium-Thiosemicarbazonates and Their Interaction with Organic Cation Transporters

A series of four water-soluble salicylaldehyde thiosemicarbazones with a positively charged trimethylammonium moiety ([H2LR]Cl, R = H, Me, Et, Ph) and four copper(II) complexes [Cu(HLR)Cl]Cl (1&ndash;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&ndash;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 &gt; 2 &gt; 4 &gt; cisplatin &gt; 1 &gt;&gt; [H2LR]Cl. The copper(II) complexes showed marked interaction with OCT1&ndash;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