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)-H2L(1)) and 3-methyl-(R)-pyrrolidine-2-carboxylate-2-formylpyridine thiosemicarbazone (D-Pro-FTSC or (R)-H2L(1)), as well as 3-methyl-(S)-pyrrolidine-2-carboxylate-2-formylpyridine 4,4-dimethyl-thiosemicarbazone (dm-L-Pro-FTSC or (S)-H2L(2)), 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 (1)H and (13)C 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 (1)H 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.
Faculty of Chemistry, Institute of Inorganic Chemistry, University of Vienna , Währinger Strasse 42, A-1090 Vienna, Austria.
Felix
F
Bacher
Orsolya
O
Dömötör
Maria
M
Kaltenbrunner
Miloš
M
Mojović
Ana
A
Popović-Bijelić
Astrid
A
Gräslund
Andrew
A
Ozarowski
Lana
L
Filipovic
Sinisa
S
Radulović
Éva A
ÉA
Enyedy
Vladimir B
VB
Arion
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008055:Lipids / Q000737:chemistry; D008670:Metals / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D012264:Ribonucleotide Reductases / Q000235:genetics / Q000378:metabolism*; D013882:Thiosemicarbazones / Q000737:chemistry* / Q000494:pharmacology*
D000970:Antineoplastic Agents; D008055:Lipids; D008670:Metals; D013882:Thiosemicarbazones; D012264:Ribonucleotide Reductases; C108427:ribonucleotide reductase R2 subunit