Mustards-Derived Terpyridine–Platinum Complexes as Anticancer Agents: DNA Alkylation vs Coordination

Abstract

The development of bifunctional platinum complexes with the ability to interact with DNA via different binding modes is of interest in anticancer metallodrug research. Therefore, we report platinum(II) terpyridine complexes to target DNA by coordination and/or through a tethered alkylating moiety. The platinum complexes were evaluated for their in vitro antiproliferative properties against the human cancer cell lines HCT116 (colorectal), SW480 (colon), NCI-H460 (non-small cell lung), and SiHa (cervix) and generally exhibited potent antiproliferative activity although lower than their respective terpyridine ligands. 1 H NMR spectroscopy and/or ESI-MS studies on the aqueous stability and reactivity with various small biomolecules, acting as protein and DNA model compounds, were used to establish potential modes of action for these complexes. These investigations indicated rapid binding of complex PtL3 to the biomolecules through coordination to the Pt center, while PtL4 in addition alkylated 9-ethylguanine. PtL3 was investigated for its reactivity to the model protein hen egg white lysozyme (HEWL) by protein crystallography which allowed identification of the N δ1 atom of His15 as the binding site.

Anthracenyl Functionalization of Half-Sandwich Carbene Complexes: In Vitro Anticancer Activity and Reactions with Biomolecules

“…Furthermore, a π-stacking interaction was observed between the imidazole-2-ylidene group and the fused benzene ring of the indole of Trp62 on a symmetry-related molecule of HEWL at a distance of 3.73 ± 0.07 Å. π-Stacking with Trp residues is a typical stabilization for complexes with aromatic ligands which interact in this pocket . Using the same method as for other metal–protein interaction studies, ,,,− our data highlight that the binding site preference and extent are determined not only by the amino acid sequence but also by the metal center and the co-ligands. , In this case, similar to what we observed for structurally related [Ru­(cym)­(1,3-dimethyl­benz­imidazole-2-ylidene)­Cl 2 ], the arene ligand was cleaved upon protein binding; however, the binding site at Asp119 is different from that of previously observed Arg14-His15, likely due to the bulkiness and lipophilic character of the anthracenyl substituent (Figure S8).…”

Platinum and Palladium Complexes as Promising Sources for Antitumor Treatments

“…The designed compounds had potent antiproliferative effects on four cancer cell lines—human colorectal (HCT116), non-small cell lung (NCI-H460), cervical (SiHa), and colon (SW480) cancer, with compound 13 exhibiting higher efficacy. Acceptable stability of the complex was proven, which provides hope for the discovery of another way to transition metal-based drugs [ 25 ].…”

BODIPY–dipicolylamine complexes of platinum(ii): X-ray structure, cellular imaging and organelle-specific near-IR light type-II PDT

“…The results indicate the formation of an adduct on binding of the EtG moiety to the platinum( ii ) centre. 12 Observation of the formation of such an adduct is of importance as these complexes exemplify a new class of platinum-based DNA cross-linking and PDT agents.…”

“…In this context, monofunctional Pt( ii ) complexes having only one labile ligand are currently drawing interest. 11,12 Unlike classical bifunctional drugs, these candidates can only bind to ds-DNA through a single co-ordination site via the ligand dissociation reaction. 13,14 Several monofunctional complexes have been reported, including [Pt(dien)Cl] + and [Pt(NH 3 ) 3 Cl] + , which have been found to be inactive towards cancer cells.…”