Novel Zn(II), Co(II) and Cu(II) diflunisalato complexes with neocuproine and their exceptional antiproliferative activity against cancer cell lines

Three novel complexes of deprotonated diflunisal (dif) with neocuproine (neo) were synthesized and characterized by elemental, spectral (UV-Vis, FTIR, fluorescence, mass spectrometry) and single-crystal X-ray diffraction analysis. Although, the compounds have a similar composition of [MCl(dif)(neo)], where M represents Zn(II) (1), Co(II) (2) and Cu(II) (3), respectively, only 1 and 2 are isostructural, while 3 differs in both molecular and supramolecular structure. In all three complex molecules, the central atom is coordinated by two nitrogen atoms of neo in bidentate chelate mode, one chlorido ligand and dif is bonded in either monodentate mode via one oxygen atom of the carboxylate in 1 and 2 or in bidentate chelate mode via both carboxylate oxygen atoms in 3. All three compounds demonstrated remarkable antiproliferative activity against human prostate (PC-3), colon (HCT116) and breast (MDA-MB-468) cancer cell lines with IC50 values in the nanomolar range, with the lowest values observed in case of PC-3 and MDA-MB-468 with 2 (20.0 nM) and 3 (31.1 nM), respectively. Moreover, complex 2, as the most active, was further investigated for its potential to induce perturbations in the cell cycle of PC-3 cells. The results indicate an induction of caspase-independent apoptosis. The interaction of the complexes with genomic DNA isolated from the respective cancer cell lines was evaluated for the intercalative mode, with the binding strength correlating with the antiproliferative activity against the PC-3 and MDA-MB-468 cancer cell lines.