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

Ruthenium-Nitrosyl Complexes with Glycine, l‑Alanine, l‑Valine, l‑Proline, d‑Proline, l‑Serine, l‑Threonine, and l‑Tyrosine: Synthesis, X‑ray Diffraction Structures, Spectroscopic and Electrochemical Properties, and Antiproliferative Activity

The reactions of [Ru­(NO)­Cl₅]^2– with glycine (Gly), l-alanine (l-Ala), l-valine (l-Val), l-proline (l-Pro), d-proline (d-Pro), l-serine (l-Ser), l-threonine (l-Thr), and l-tyrosine (l-Tyr) in <i>n</i>-butanol or <i>n</i>-propanol afforded eight new complexes (<b>1</b>–<b>8</b>) of the general formula [RuCl₃(AA–H)­(NO)]⁻, where AA = Gly, l-Ala, l-Val, l-Pro, d-Pro, l-Ser, l-Thr, and l-Tyr, respectively. The compounds were characterized by elemental analysis, electrospray ionization mass spectrometry (ESI-MS), ¹H NMR, UV–visible and ATR IR spectroscopy, cyclic voltammetry, and X-ray crystallography. X-ray crystallography studies have revealed that in all cases the same isomer type (from three theoretically possible) was isolated, namely <i>mer</i>(Cl),<i>trans</i>(NO,O)-[RuCl₃(AA–H)­(NO)], as was also recently reported for osmium analogues with Gly, l-Pro, and d-Pro (see <i>Z. Anorg. Allg. Chem.</i> <b>2013</b>, <i>639</i>, 1590–1597). Compounds <b>1</b>, <b>4</b>, <b>5</b>, and <b>8</b> were investigated by ESI-MS with regard to their stability in aqueous solution and reactivity toward sodium ascorbate. In addition, cell culture experiments in three human cancer cell lines, namely, A549 (nonsmall cell lung carcinoma), CH1 (ovarian carcinoma), and SW480 (colon carcinoma), were performed, and the results are discussed in conjunction with the lipophilicity of compounds