Structures and anticancer activity of chlorido platinum(II) saccharinate complexes with mono- and dialkylphenylphosphines

cis-[PtCl(sac)(PPh2Me)2] (1), cis-[PtCl(sac)(PPhMe2)2] (2), trans-[PtCl(sac)(PPh2Et)2] (3) and trans-[PtCl(sac)(PPhEt2)2] (4) complexes (sac = saccharinate) were synthesized and characterized by elemental analysis and spectroscopic methods. The structures of 2–4 were determined by X-ray single-crystal diffraction. The interaction of the complexes with DNA was studied various biochemical, biophysical and molecular docking methods. Only the cis-configured complexes (1 and 2) showed nuclease activity and their binding affinity towards DNA was considerably higher than those of their trans-congeners (3 and 4). The chlorido ligand in the cis-configured complexes underwent aquation, making them more reactive towards DNA. Furthermore, 1 and 2 exhibited anticancer potency on breast (MCF-7) and colon (HCT116) cancer cells similar to cisplatin, whereas 3 and 4 were biologicallly inactive. Mechanistic studies on MCF-7 cells showed that higher nuclear uptake, cell cycle arrest at the S phase, dramatically increased DNA double-strand breaks, apoptosis induction, elevated levels of reactive oxygen species (ROS) and high mitochondrial membrane depolarization greatly contribute to the anticancer potency of 1 and 2. cis-[PtCl(sac)(PPh2Me)2] and cis-[PtCl(sac)(PPhMe2)2] (sac = saccharinate) are highly cytotoxic, whereas their trans-congeners with PPh2Et and PPhEt2 are biologically inactive. The cis-configured complexes undergo aquation and cause cell arrest at the S phase and the generation of excessive reactive oxygen species, damaging to both mitochondria and DNA. [Display omitted] •Synthesis of new cis−/trans-configured Pt(II) saccharinate complexes of monophosphines.•Excellent anticancer activity of cis-complexes against breast and colon cancer cells•cis-complexes show higher nuclease activity and nuclear uptake due to hydrolysis.•cis-complexes induce apoptotic cell death.•cis-complexes cause mitochondrial dysfunction and DNA double-strand breaks.