Abstract
We report the synthesis, characterization, and antiproliferative activity of organo-osmium(II) and organo-ruthenium(II) half-sandwich complexes [(η6-p-cym)Os(L)Cl]Cl (1 and 2) and [(η6-p-cym)Ru(L)Cl]Cl (3 and 4), where L = N-(2-hydroxy)-3-methoxybenzylidenethiosemicarbazide (L1) or N-(2,3-dihydroxybenzylidene)-3-phenylthiosemicarbazide (L2), respectively. X-ray crystallography showed that all four complexes possess half-sandwich pseudo-octahedral “three-legged piano-stool” structures, with a neutral N,S-chelating thiosemicarbazone ligand and a terminal chloride occupying three coordination positions. In methanol, E/Z isomerization of the coordinated thiosemicarbazone ligand was observed, while in an aprotic solvent like acetone, partial dissociation of the ligand occurs, reaching complete displacement in a more coordinating solvent like DMSO. In general, the complexes exhibited good activity toward A2780 ovarian, A2780Cis cisplatin-resistant ovarian, A549 lung, HCT116 colon, and PC3 prostate cancer cells. In particular, ruthenium complex 3 does not present cross-resistance with the clinical drug cisplatin in the A2780 human ovarian cancer cell line. The complexes were more active than the free thiosemicarbazone ligands, especially in A549 and HCT116 cells with potency improvements of up to 20-fold between organic ligand L1 and ruthenium complex 1.
Highlights
The discovery of highly efficient anticancer drugs with increased selectivity and less toxic side effects is an area of intense research in bioinorganic chemistry.[1]
Thiosemicarbazones (TSCs) and their metal complexes display a wide spectrum of biological activities,[2−5] in particular they possess anticancer, antibacterial, and antiviral properties.[6−8] A variety of cellular mechanisms of action appears to be involved in the activity of this class of ligands,[9] including the inhibition of cellular iron uptake by transferrin,[10−12] the mobilization of iron from cells,[6−8] the inhibition of ribonucleotide reductase activity,[13−15] the up-regulation of the metastasis suppressor protein, N-myc downstream regulated gene I,16,17 and the formation of redox active metal complexes that produce reactive oxygen species.[11,18−20] various studies[21] have demonstrated that the biological properties of TSC ligands can be modified and improved upon binding to transition metal ions.[6,22]
Metal complexes of TSCs are playing a promising role in anticancer research, as is evident from the number of recent publications.[8,25−27] Platinum drugs are still widely used to treat cancer,[5,28] but their therapeutic use can be limited by intrinsic or acquired resistance and by the occurrence of numerous deleterious side effects.[29,30]
Summary
The discovery of highly efficient anticancer drugs with increased selectivity and less toxic side effects is an area of intense research in bioinorganic chemistry.[1]. A second row transition metal, continues to attract much attention,[31,32] as its complexes have long been known to be well-suited for biological applications.[33,34] Organometallic Ru(II) complexes with half-sandwich structure have demonstrated antiproliferative potential,[35] and there are numerous possibilities to modulate their biological and pharmacological properties by the appropriate choice of the ligands.[11,36] In particular, the presence of a chelating ligand offers structural stability and the opportunity to tune the electronic and steric features of the complex.[37] Additional features to be considered include water solubility and air stability.[37,38] The biological activity of osmium compounds has been much less explored, perhaps because of the reputation of osmium (as osmium tetroxide) as being highly toxic.[39] several half-sandwich piano-stool
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