Unprecedented formation of palladium(II)-pyrazole based thiourea from chromone thiosemicarbazone and [PdCl2(PPh3)2]: Interaction with biomolecules and apoptosis through mitochondrial signaling pathway

Abstract

Two novel pyrazole based thiourea palladium(II) complexes, [PdCl(PPh₃)(C₉H₈NO₂S-pz)] (1) and [PdCl(PPh₃)(C₁₄H₁₀NO₂S-pz)] (2) [pz = pyrazole (C₃H₂N₂)] have been obtained unexpectedly from chromone thiosemicarbazones (L1 and L2) and [PdCl₂(PPh₃)₂]. The compounds have been fully characterized by physicochemical studies. The single crystal X-ray diffraction and spectral studies revealed square planar geometry for the complexes. The conversion of chromone thiosemicarbazone into pyrazole based thiourea might have happened through coordination to palladium(II) ion after enolization, Michael addition and ring opening followed by cyclization. To the best of our knowledge, this is the first report for the conversion of chromone thiosemicarbazone into pyrazole based thiourea moiety. Plausible mechanism was proposed based on the spectroscopic studies. Calf thymus (CT) DNA binding of the compounds was explored using various spectroscopic and molecular docking methods. DNA cleavage studies suggested that complexes 1 and 2 had the capacity to cleave the supercoiled DNA (pUC19) to its naked form. In vitro cytotoxic property of the ligands and complexes has been evaluated against three human cancer cells such as A549, HepG-2 and U937. Complex 2 exhibited potent cytotoxic activity against HepG-2 cells with the IC₅₀ value of 10.4 μM. In addition, mechanistic studies showed that complex 2 induced apoptosis through mitochondrial signaling pathway in HepG-2 cells. Beneficially, complex 2 showed less toxicity against human lung (IMR90) normal cells and hence it emerges as a potential candidate for further studies.

Keywords: Apoptosis; Biomolecules; Cytotoxicity; Michael addition; Mitochondrial signaling pathway; Palladium(II).