Copper(II) Complexes with Highly Water-Soluble l- and d‑Proline–Thiosemicarbazone Conjugates as Potential Inhibitors of Topoisomerase IIα

Two
proline–thiosemicarbazone bioconjugates with excellent aqueous
solubility, namely, 3-methyl-(S)-pyrrolidine-2-carboxylate-2-formylpyridine
thiosemicarbazone [l-Pro-FTSC or (S)-H2L] and 3-methyl-(R)-pyrrolidine-2-carboxylate-2-formylpyridine
thiosemicarbazone [d-Pro-FTSC or (R)-H2L], have been synthesized and characterized by elemental analysis,
one- and two-dimensional 1H and 13C NMR spectroscopy,
and electrospray ionization mass spectrometry. The complexation behavior
of l-Pro-FTSC with copper­(II) in an aqueous solution and
in a 30% (w/w) dimethyl sulfoxide/water mixture has been studied via
pH potentiometry, UV–vis spectrophotometry, electron paramagnetic
resonance, 1H NMR spectroscopy, and spectrofluorimetry.
By the reaction of copper­(II) acetate with (S)-H2L and (R)-H2L in water, the complexes
[Cu­(S,R)-L] and [Cu­(R,S)-L] have been synthesized and comprehensively
characterized. An X-ray diffraction study of [Cu­(S,R)-L] showed the formation of a square-pyramidal
complex, with the bioconjugate acting as a pentadentate ligand. Both
copper­(II) complexes displayed antiproliferative activity in CH1 ovarian
carcinoma cells and inhibited Topoisomerase IIα activity in
a DNA plasmid relaxation assay.