Synthesis, characterization, DNA binding, topoisomerase I inhibition and antiproliferation activities of three new functionalized terpyridine platinum(II) complexes

Platinum(terpyridine) complexes with N-heterocyclic carbene co-ligands: high antiproliferative activity and low toxicityin vivo

“…20 In the cases of 2a′ and [Pt( a )Cl]Cl, the potency dropped by approximately an order of magnitude compared to a , while the antiproliferative activity of 2b was similar to that of b . When it comes to the impact of the NHC co-ligand, substitution of the chlorido ligand in [Pt(tpy)Cl] + complexes with NH 3 or PPh 3 led to equivalent activity or slight increases in potency, 28 similar to what was found for NHC complex 2a′ and its chlorido analogue [Pt( a )Cl]Cl (Table 1).…”

“…20 To investigate the capability of 2b to interact with DNA, we used the DNA shift assay with a circular plasmid DNA. This assay has been used frequently for metal complexes, including Pt and tpy complexes, 28,30–39 and usually the DNA is stained with ethidium bromide (EtBr) post-electrophoresis, which allows for intact DNA–metal-based complex analysis regardless of the nature of interaction, i.e. , covalent or intercalative.…”

“…, covalent or intercalative. 28,30–39 However, EtBr can also be embedded in the gel matrix to investigate DNA intercalation as EtBr would displace the intercalating metal complex. 37…”

“…With a phenyl-substituted tpy ligand, we identified the dicationic Pt(tpy)(NHC) complex [Pt( b )(NHC)] 2+ ( 2b ) as a highly antiproliferative agent in a small panel of cell lines compared to previously reported structurally-related complexes. 16,20,28,36,39 However, it is important to note that the IC 50 values of most of these compounds were determined under different conditions. 16,28,36,39 In fact, complex 2b was orders of magnitude more potent than 2a′ , due to significantly higher cellular accumulation, and its chlorido analogue [Pt( a )Cl]Cl and had similar activity as its tpy ligand, demonstrating the importance of tpy ligands on the activity.…”

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

“…Such alternative DNA-binding modes have been proposed to result in nonconventional modes of action and may be a means to overcome resistance often observed in the treatment of cancer patients . In addition to the formation of covalent dative bonds or electrostatic interactions, not only metal complexes but also organic drugs have been designed to interact with DNA through intercalation between DNA bases. − This is a feature of planar complexes, and planarity can be introduced by the use of large aromatic ancillary ligands such as derivatives of 2,2′:6′,2″-terpyridine (tpy) and acridine. ,,− While the latter have been used as substituents with a long linker between the Pt center and the intercalator, tpy can act as a tridentate chelator, and the Pt center becomes part of the planar structure. The former strategy results in bifunctional platinum complexes, where the Pt center is able to bind covalently to DNA in the classic way, while acridine intercalates into DNA and thereby forms unconventional DNA adducts.…”