Synthesis, structural characterisation and biological studies of new mononuclear platinum(II) complexes with sterically hindered heterocyclic ligands

Abstract

a b s t r a c tThree novel cisplatin analogues were synthesized, designed according to an approach which violates the ''classical'' structure-activity relationship, by replacing the diamine ligands with a planar N donor heterocycle giving a sterically hindered complex. Moreover, the sterical hindrance of antitumor drug candidates potentially makes them less susceptible to deactivation by sulphur-containing proteins and helping to overcome resistance mechanisms. The resulting mononuclear complexes of sterically hindered polidentate heterocyclic N ligands [PtCl(bbp)have been prepared and structurally characterised. Both neutral and ionic complexes are present, with monofunctional (1) and bifunctional Pt(II) moieties (2) and coordinatively saturated Pt(II) ions in the mixed ligand complex (3), whose size and shape enable them to behave as novel scaffolds for DNA binding. All complexes were tested ''in vitro'' for their biological activity on human HT29 colorectal carcinoma and HepG2 hepatoma cells. The complexes (1) and (3), endowed with a positive charge, showed a potent cytotoxic activity and reduced cell viability with an efficacy higher than that of cisplatin; whilst the neutral bifunctional compound (2) was inactive. IC50 values have been calculated for the active compounds. The cytotoxic effects were confirmed by the accumulation of treated cells in subG0/G1 phase of cell cycle, by the loss of mitochondrial potential (Dw m ) and by the chromatin condensation or fragmentation observed by means of fluorescence microscopy after Hoechst 33258 nuclear staining. A study on intracellular platinum uptake in HT29 cell line has been also performed and data obtained strongly suggest that the cytotoxicity of new tested complexes reported in this work is based on a different pharmacodynamic pattern with respect to cisplatin.

Palladium(II) Complexes of Ambidentate and Potentially Cyclometalating 5‐Aryl‐3‐(2′‐pyridyl)‐1,2,4‐triazine Ligands

“…The 5‐aryl‐3‐(2′‐pyridyl)‐1,2,4‐triazine moieties themselves have been used for decades as versatile ligands for transition‐metal complexes with some medical or technical applications. The most important application is probably that of 3‐(2‐pyridyl)‐5,6‐diphenyl‐1,2,4‐triazine‐ p , p′ ‐disulfonic acid [PyTZ(HO 2 SOPh) 2 ], following the nomenclature in Scheme , also called FerroZine™, for the colorimetric detection of Fe II in biological or other systems .…”

“…Another important application is the use of the potentially tri‐, tetra‐ or pentadentate 2,6‐bis(5,6‐dipyridyl‐1,2,4‐triazinyl)pyridine ligands for the extraction of lanthanides or actinides . Interestingly, complexes of 3‐(2′‐pyridyl)‐1,2,4‐triazine ligands with Group 10 elements are scarce . This is strange, since the abovementioned triazinyl‐containing polypyridine ligands are especially attractive for masking the corrosion and fission products Ni II and Pd II in the extraction of actinides, for example, in the PUREX process,, , and Pt II complexes of 3‐(2′‐pyridyl)‐1,2,4‐triazine ligands have been studied for their cytotoxic or antiviral properties .…”

“…Interestingly, complexes of 3‐(2′‐pyridyl)‐1,2,4‐triazine ligands with Group 10 elements are scarce . This is strange, since the abovementioned triazinyl‐containing polypyridine ligands are especially attractive for masking the corrosion and fission products Ni II and Pd II in the extraction of actinides, for example, in the PUREX process,, , and Pt II complexes of 3‐(2′‐pyridyl)‐1,2,4‐triazine ligands have been studied for their cytotoxic or antiviral properties . Very recently, the binuclear complex [Pd 2 (NO 3 ) 4 (C9BTBP)] · 2.5H 2 O {C9BTBP = 6,6′‐bis[5,6‐di(nonyl)‐1,2,4‐triazin‐3‐yl]‐2,2′‐bipyridine} was synthesised and characterised by elemental analysis, DSC‐TGA and 1 H NMR spectroscopy in a report dedicated to the separation of Pd II from minor actinides .…”

Platinum in indoor settled dust matter (homes and cars)

“…Information of the acute toxicity of some Pt-chlorinated salts and evidence of DNA damage due to Pt exposure have been observed both in vitro and in vivo [38]. Only few compounds (cisplatin, and carboplatin, etc) are used as antineoplastic agents in the medical treatment of several tumors [39,40].…”

Spectroscopic Studies, Biological Activity, and Cytotoxicity of Some Binary and Ternary Palladium and Platinum Complexes of Certain Heterocyclic Ligands

“…Interest in transition metal complexes of heterocyclic compounds containing nitrogen as a donor atom such as pyridines, bi-and polypyridines, 2-(2 0 -pyridyl)-benzimidazole, 2-pyrazinecarboxylic acid, 2-pyrazinecarboxamide, and 2-aminobenzimidazole have a vital role in biology. [5][6][7][8][9][10] Some azines act as anticancer agents. All the previously investigated activities of platinum complexes as antitumor were of the cisplatin analogues where the platinum is bound to one type of nitrogen ligand (binary complexes).…”