EPR and electrochemical interpretation of bispyrazolylacetate anchored Ni(ii) and Mn(ii) complexes: cytotoxicity and anti-proliferative activity towards human cancer cell lines

Abstract

Two mononuclear Ni^II and Mn^II compounds, [Ni(bdtbpza)₂(CH₃OH)₄] (1) and [Mn(bdtbpza)₂(CH₃OH)₂(H₂O)₂] (2), are afforded by employing a ‘scorpionate’ type precursor [bdtbpza = bis(3,5-di-t-butylpyrazol-1-yl)acetate]. The single crystal X-ray structure reveals that the central metal ion (Ni^II for 1 and Mn^II for 2) is surrounded by a pair of O_acetate atoms of two bis(pyrazol-1-yl)acetate units, while four O_MeOH donors for 1 and two O_MeOH plus two O_water for 2 complete the first coordination sphere. Thus, both compounds exhibit a slightly distorted octahedral geometry possessing an O₆ coordination environment. EPR spectra of Cu^II-doped 1 and of 2 recorded on the polycrystalline solids and in organic solution confirm the octahedral geometry around the metal ions and the binding of six oxygen atoms. The electrochemical study of compounds 1 and 2 shows that one electron reduction of Mn^II occurs at a more negative potential than Ni^II, indicating a lower tendency of reduction for Mn than Ni. Both compounds displayed a high cytotoxic activity against A2780 ovarian carcinoma cells and no cytotoxic activity in normal primary human fibroblasts for concentrations up to 55 μM. Notwithstanding, compound 1 is found to be the most cytotoxic towards A2780 cancer cells. The cytotoxic activity of compound 1 is correlated with the induction of apoptosis associated with a higher mitochondria dysfunction and autophagy cell death. In addition, the compounds can induce oxidative damage leading to ROS accumulation. Overall, the data presented here demonstrate that 1 has potential for further in vivo studies aiming at its future application in ovarian cancer therapy.