Effects of Terminal Dimethylation and Metal Coordination of Proline-2-formylpyridine Thiosemicarbazone Hybrids on Lipophilicity, Antiproliferative Activity, and hR2 RNR Inhibition

The nickel­(II), copper­(II), and zinc­(II) complexes of the proline-thiosemicarbazone hybrids 3-methyl-(<i>S</i>)-pyrrolidine-2-carboxylate-2-formylpyridine thiosemicarbazone (l-Pro-FTSC or (<i>S</i>)-H₂L¹) and 3-methyl-(<i>R</i>)-pyrrolidine-2-carboxylate-2-formylpyridine thiosemicarbazone (d-Pro-FTSC or (<i>R</i>)-H₂L¹), as well as 3-methyl-(<i>S</i>)-pyrrolidine-2-carboxylate-2-formylpyridine 4,4-dimethyl-thiosemicarbazone (dm-l-Pro-FTSC or (<i>S</i>)-H₂L²), namely, [Ni­(l-Pro-FTSC–2H)]₂ (<b>1</b>), [Ni­(d-Pro-FTSC–2H)]₂ (<b>2</b>), [Ni­(dm-l-Pro-FTSC–2H)]₂ (<b>3</b>), [Cu­(dm-l-Pro-FTSC–2H)] (<b>6</b>), [Zn­(l-Pro-FTSC–2H)] (<b>7</b>), and [Zn­(d-Pro-FTSC–2H)] (<b>8</b>), in addition to two previously reported, [Cu­(l-Pro-FTSC–2H)] (<b>4</b>), [Cu­(d-Pro-FTSC–2H)] (<b>5</b>), were synthesized and characterized by elemental analysis, one- and two-dimensional ¹H and ¹³C NMR spectroscopy, circular dichroism, UV–vis, and electrospray ionization mass spectrometry. Compounds <b>1</b>–<b>3</b>, <b>6</b>, and <b>7</b> were also studied by single-crystal X-ray diffraction. Magnetic properties and solid-state high-field electron paramagnetic resonance spectra of <b>2</b> over the range of 50–420 GHz were investigated. The complex formation processes of l-Pro-FTSC with nickel­(II) and zinc­(II) were studied in aqueous solution due to the excellent water solubility of the complexes via pH potentiometry, UV–vis, and ¹H NMR spectroscopy. The results of the antiproliferative activity <i>in vitro</i> showed that dimethylation improves the cytotoxicity and hR2 RNR inhibition. Therefore, introduction of more lipophilic groups into thiosemicarbazone-proline backbone becomes an option for the synthesis of more efficient cytotoxic agents of this family of compounds