Platinum(ii) O,S complexes as potential metallodrugs against Cisplatin resistance

Abstract

We report on platinum(ii) complexes with different cinnamic acid derivatives as ligands with cytotoxic activity against Cisplatin resistant ovarian cancer cell line subcultures of SKOV3 and A2780. A typical mechanism of action for platinum(ii) complexes as Cisplatin itself is binding to the DNA and inducing double-strand breaks. We examined the biological behavior of these potential drugs with 9-methylguanine using NMR spectroscopic methods and their DNA damage potential including γH2AX-foci analyses. X-ray diffraction methods have been used to elucidate the molecular structures of the platinum(ii) complexes. Interactions with the model protein lysozyme have been evaluated by different techniques including UV-Vis absorption spectroscopy, fluorescence and X-ray crystallography.

Platinum(II) O,S Complexes Inhibit the Aggregation of Amyloid Model Systems

“…Indeed, spectra of NPM1 264–277 in the presence of the Pt compounds show minima at wavelengths ≤210 nm (Figure 7a), which are diagnostic of the presence of a significant helical content and suggest the formation of ligand-specific secondary structures. A similar behavior has been previously observed when other Pt compounds interacted with Aβ peptides [42].…”

“…Here we focus our attention on a series of Pt(II) compounds bearing a conserved O , S binding moiety, based on β-hydroxy dithiocinnamic esters, as a bidentate ligand (Figure 1). These compounds are appreciably stable in mixed dimethyl sulfoxide−aqueous solvents [11] and cytotoxic for cisplatin resistant cell lines, suggesting a different MOA when compared to cisplatin [42]. To investigate the inhibitory potentials of these molecules on the aggregation of amyloid peptides, we employed three different sequences: (1) the peptide fragment corresponding to the helix H2 (residues 264–277) of C-terminal domain of nucleophosmin 1 (NPM1 264–277 ), which shows a remarkable tendency to form amyloid-like assemblies endowed with fibrillar morphology and β-sheet structure toxic to neuroblastoma cells [43,44,45,46,47,48], (2) the heptapetide GNNQQNY, spanning residues 7–13 of the Yeast Prion Protein Sup35p (Sup35p 7–13 ), which is involved in the aggregation of Sup35p [49] and (3) the fragment consisting of residues 21–40 of Aβ (Aβ 21–40 ) [50].…”

Novel Nickel(II), Palladium(II), and Platinum(II) Complexes with O,S Bidendate Cinnamic Acid Ester Derivatives: An In Vitro Cytotoxic Comparison to Ruthenium(II) and Osmium(II) Analogues

“…All β-hydroxydithiocinnamic acid esters L1–L6 were synthesized and characterized as described previously [ 18 , 50 ]. Ligands L1–L6 were diluted in 15 mL acetonitrile in a flask and deprotonated with sodium acetate, and the corresponding metal salt was added.…”

“…Non-classical compounds are designed to focus on different mechanisms of action, e.g., trans-compounds or monofunctional complexes, as well as platinum(II) molecules which do not bind covalently to the DNA, for example metallointercalators, which are able to intercalate in the DNA [ 2 , 14 , 17 ]. We recently reported on platinum(II) complexes bearing an O , S -bidendate ligand, DMSO (dimethylsulfoxide) and one chloride as a leaving group with promising results on cisplatin resistant cell lines, and on their interaction with targets other than the DNA [ 18 , 19 , 20 ].…”

Synthesis and evaluation of platinum complexes with potential antitumor activity

“…Besides, the design of new platinum-based anti-cancer agents might help to overcome cisplatin resistance. The search for new platinum complex is an ever present issue because of the potential of this class of compounds as antitumor agents (Hildebrandt et al, 2016;Lakomska et al, 2016;Pollak, Goddard, Porschke, 2016;Popova et al, 2016;Rehm et al, 2016;Wang et al, 2016).…”