New Iminodiacetate–Thiosemicarbazone Hybrids and Their Copper(II) Complexes Are Potential Ribonucleotide Reductase R2 Inhibitors with High Antiproliferative Activity

As ribonucleotide
reductase (RNR) plays a crucial role in nucleic acid metabolism, it
is an important target for anticancer therapy. The thiosemicarbazone
Triapine is an efficient R2 inhibitor, which has entered ∼20
clinical trials. Thiosemicarbazones are supposed to exert their biological
effects through effectively binding transition-metal ions. In this
study, six iminodiacetate–thiosemicarbazones able to form transition-metal
complexes, as well as six dicopper­(II) complexes, were synthesized
and fully characterized by analytical, spectroscopic techniques (IR,
UV–vis; 1H and 13C NMR), electrospray
ionization mass spectrometry, and X-ray diffraction. The antiproliferative
effects were examined in several human cancer and one noncancerous
cell lines. Several of the compounds showed high cytotoxicity and
marked selectivity for cancer cells. On the basis of this, and on
molecular docking calculations one lead dicopper­(II) complex and one
thiosemicarbazone were chosen for in vitro analysis as potential R2
inhibitors. Their interaction with R2 and effect on the Fe­(III)2-Y· cofactor were characterized by microscale thermophoresis,
and two spectroscopic techniques, namely, electron paramagnetic resonance
and UV–vis spectroscopy. Our findings suggest that several
of the synthesized proligands and copper­(II) complexes are effective
antiproliferative agents in several cancer cell lines, targeting RNR,
which deserve further investigation as potential anticancer drugs.