Five-Coordinate Platinum(II) Compounds Containing Sugar Ligands: Synthesis, Characterization, Cytotoxic Activity, and Interaction with Biological Macromolecules

Abstract

This article describes the synthesis and characterization of novel cationic five-coordinate Pt(II) complexes containing nitrogen sugar-based ligands. The cytotoxicity of the complexes was evaluated on different cell lines with the expectation that both the coordinative saturation and the sugar moiety cooperate to enhance their biological activity. In fact, the complexes resulted to be more active than cisplatin but still with little selectivity. They activate the apoptosis pathway. Binding of representative compounds with DNA was studied by ethidium bromide displacement assay and circular dichroism. Binding to model proteins was also investigated; the X-ray structure of the adduct formed in the reaction between a representative compound and the model protein bovine pancreatic ribonuclease was obtained. The structure discloses an unprecedented interaction between a five-coordinate Pt(II) moiety and a His side chain.

Synthesis, Antiproliferative Activity, and DNA Binding Studies of Nucleoamino Acid-Containing Pt(II) Complexes

“…Taken together, the CD data suggested that DNA can be a possible target of the newly obtained compounds, similar to other well-known anticancer Pt complexes [ 6 , 7 , 12 , 21 , 23 , 47 , 48 ], with the DAP(T)-based Pt complexes inducing important conformational changes in G4 structures and single stranded ODNs upon binding, contrarily to the duplex structure (either containing or not the GG box).…”

“…Their interaction in solution was investigated with four DNA model systems, i.e., a random coil single strand, two B form-duplexes, one with and the other without a GG box, and a G-quadruplex structure. From CD binding experiments, it emerged that DNA can be a possible target of these brand new compounds, similar to other reported bioactive Pt complexes (as well as transition metal complexes, such as ruthenium complexes) [ 6 , 7 , 12 , 15 , 21 , 23 , 47 , 48 , 52 , 53 ]. In particular, we observed significant changes only in the CD spectrum of the single strand and G4 when T1 and T2 were added to each DNA system, evidencing that both the complexes interacted with these oligonucleotides.…”

“…The drawbacks and side effects of cisplatin treatment [ 1 , 2 ] have stimulated the design and synthesis of new anticancer Pt-based drugs with the aim of obtaining compounds more effective and less toxic than CDDP. Thus, in the last decades, a wide variety of Pt complexes have been tested for antiproliferative activity [ 5 , 6 , 7 ]. Some have also entered in clinical trials, but only a few have been approved for clinical use.…”

“…As ligands to be incorporated in Pt-based complexes, most studies focused on bioactive molecules, such as peptides [ 8 ], carbohydrates [ 7 , 9 ], fatty acids [ 10 , 11 ], amino acids (both proteinogenic or not) [ 8 , 12 ], nucleosides, nucleotides [ 13 , 14 , 15 ], and natural products [ 16 ], to obtain compounds with enhanced activity thanks to the synergistic effects of the Pt ion and the bioactive ligand. Since the aforementioned bioactive molecules are widespread in living organisms, when used as Pt(II) ligands, the metal center can be masked, retarding the complex deactivation or avoiding its recognition by a specific protein.…”

Crystal structures of three platinacyclic complexes bearing isopropyl eugenoxyacetate and pyridine derivatives

“…Although platinum-based drugs have dominated the treatment of various cancers by chemical agents, the research on new platinum(ll) complexes for the purpose of medical application is still attractive for the worldwide scientific society (Johnstone et al, 2016). Recently, numerous platinum(ll) complexes bearing alkene and pyridine derivatives have been synthesized and tested for their anti-cancer activities (Bigioni et al, 2000;Da et al, 2012Da et al, , 2015Chi et al, 2017Chi et al, , 2018Cucciolito et al, 2018;Dodoff et al, 2012). Nevertheless, crystal data for these complexes are limited, some examples being the crystal structures of [PtCl(eugenol-1H)(pyridine)], [PtCl(eugenol-1H)(4-methylpyridine)] (Chi et al, 2018) and trans-[PtCl 2 (C 2 H 4 )(N-3-pyridinylmethanesulfonamide)] (Dodoff et al, 2012).…”