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-(S)-pyrrolidine-2-carboxylate-2-formylpyridine thiosemicarbazone
(l-Pro-FTSC or (S)-H2L1) and 3-methyl-(R)-pyrrolidine-2-carboxylate-2-formylpyridine
thiosemicarbazone (d-Pro-FTSC or (R)-H2L1), as well as 3-methyl-(S)-pyrrolidine-2-carboxylate-2-formylpyridine
4,4-dimethyl-thiosemicarbazone (dm-l-Pro-FTSC or (S)-H2L2), namely, [Ni­(l-Pro-FTSC–2H)]2 (1), [Ni­(d-Pro-FTSC–2H)]2 (2), [Ni­(dm-l-Pro-FTSC–2H)]2 (3), [Cu­(dm-l-Pro-FTSC–2H)]
(6), [Zn­(l-Pro-FTSC–2H)] (7), and [Zn­(d-Pro-FTSC–2H)] (8), in addition
to two previously reported, [Cu­(l-Pro-FTSC–2H)] (4), [Cu­(d-Pro-FTSC–2H)] (5),
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 1–3, 6, and 7 were also studied by single-crystal
X-ray diffraction. Magnetic properties and solid-state high-field
electron paramagnetic resonance spectra of 2 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 in vitro 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.