Novel heteronuclear Pt (II)‐L‐Zn (II) complexes: synthesis, interactions with biomolecules, cytotoxic properties. Two metals give promising antitumor activity?

Abstract

The novel heteronuclear complexes [{cis‐PtCl (NH3)(μ‐pyrazine)ZnCl (terpy)}](ClO4)2 (Pt‐L1‐Zn) and [{cis‐PtCl (NH3)(μ‐4,4′‐bipyridyl)ZnCl (terpy)}](ClO4)2 (Pt‐L2‐Zn) (where terpy = 2,2′:6′,2′′‐terpyridine, L1 = pyrazine, L2 = 4,4′‐bipyridyl) were synthesized and characterized. The pKa values were determined, and based on them it was established that the π‐acceptor ability of the pyrazine bridging ligand is more affective on lower pKa values. The kinetic measurements of the substitution reactions with biologically relevant ligands, such as guanosine‐5′‐monophosphate (5′‐GMP), inosine‐5′‐monophosphate (5′‐IMP) and glutathione (GSH), were studied at pH 7.4. The reactions were followed under pseudo‐first‐order conditions by UV–Vis spectrophotometry. The order of reactivity of the investigated biomolecules for the first reaction is 5′‐GMP > 5′‐IMP > GSH, while for the second is 5′‐IMP > GSH. Pt‐L1‐Zn complex is more reactive than Pt‐L2‐Zn. The cytotoxic activity of heteronuclear Pt‐L1‐Zn and Pt‐L2‐Zn complexes was determined on human colorectal cancer cell line (HCT‐116) and human breast cancer cell line (MDA‐MB‐231). Both complexes significantly reduced cell viability on tested cell lines and exerted significant cytotoxic effects, with better effect on HCT‐116 cells than cisplatin, especially after 72 hr (IC50 < 0.52 μM). The Pt‐L2‐Zn complex showed higher activity against human breast cancer cells (MDA‐MB‐231) than cisplatin after 72 hr. The higher reactivity toward DNA constituent and significant cytotoxic activity may be attributed to the different geometry, Lewis acidity of different metal centers, as well as, to choice of bridging ligands.

Modes of Interactions with DNA/HSA Biomolecules and Comparative Cytotoxic Studies of Newly Synthesized Mononuclear Zinc(II) and Heteronuclear Platinum(II)/Zinc(II) Complexes toward Colorectal Cancer Cells

“…Our recent studies indicate that heteronuclear complexes with adopted general formula cis - or trans -Pt-L-Zn are more reactive toward DNA constituents than sulfur-containing biomolecules. These complexes have demonstrated significantly higher cytotoxicity compared to cisplatin [ 10 , 11 ]. The increased cytotoxicity may be attributed to potential interference with multiple intracellular processes and structures that incorporate the zinc(II) ion.…”

“…The increased cytotoxicity may be attributed to potential interference with multiple intracellular processes and structures that incorporate the zinc(II) ion. The molecular mechanisms governing the response of the colorectal cancer cell line HCT116 to the cytotoxic action of these complexes appear to be complex, involving intricate interplays between various signaling pathways [10][11][12].…”

Comparative Cheminformatics Study on Structural and Physiological Similarity of Bridged Heterometallic Complexes

“…For example, they have been quite helpful in bimetallic catalytic processes, whereas a two-metal catalyst can perform two or more mechanistically distinct transformations [1,2]. Also, their significantly increased antitumor activity, compared to cisplatin, makes them potential drug candidates [3].…”

“…Generally, incorporating different metal ions that differ in Lewis acidity has a synergic effect [4]. The compounds of two metal ions with distinct coordination geometry and kinetic properties will have distinguishable affinity and reactivity towards biologically relevant nucleophiles [3][4][5]. The ability to coordinate into diverse geometries depending on the specific arrangement of donor atoms in biomolecules increases the cytotoxicity of these molecules [3,6].…”

“…The compounds of two metal ions with distinct coordination geometry and kinetic properties will have distinguishable affinity and reactivity towards biologically relevant nucleophiles [3][4][5]. The ability to coordinate into diverse geometries depending on the specific arrangement of donor atoms in biomolecules increases the cytotoxicity of these molecules [3,6]. All of this has caused the flourishing of the chemistry of the heterometallic complexes.…”