Ionic mononuclear [Fe] and heterodinuclear [Fe,Ru] bis(diphenylphosphino)alkane complexes: Synthesis, spectroscopy, DFT structures, cytotoxicity, and biomolecular interactions.

Iron(II) and Ru(II) half-sandwich compounds encompass some promising pre-clinical anticancer agents whose efficacy may be tuned by structural modification of the coordinated ligands. Here, we combine two such bioactive metal centres in cationic bis(diphenylphosphino)alkane-bridged heterodinuclear [Fe ²⁺ , Ru ²⁺ ] complexes to delineate how ligand structural variations modulate compound cytotoxicity. Specifically, Fe(II) complexes of the type [(η ⁵ -C ₅ H ₅ )Fe(CO) ₂ (κ ¹ -PPh ₂ (CH ₂ ) _n PPh ₂ )]{PF ₆ } (n = 1-5), compounds 1-5, and heterodinuclear [Fe ²⁺ , Ru ²⁺ ] complexes, [(η ⁵ -C ₅ H ₅ )Fe(CO) ₂ (μ-PPh ₂ (CH ₂ ) _n PPh ₂ ))(η ⁶ -p-cymene)RuCl ₂ ]{PF ₆ } (n = 2-5) (compounds 7-10), were synthesized and characterised. The mononuclear complexes were moderately cytotoxic against two ovarian cancer cell lines (A2780 and cisplatin resistant A2780cis) with IC ₅₀ values ranging from 2.3 ± 0.5 μM to 9.0 ± 1.4 μM. For 7-10, the cytotoxicity increased with increasing Fe⋅⋅⋅Ru distance, consistent with their DNA affinity. UV-visible spectroscopy suggested the chloride ligands in heterodinuclear 8-10 undergo stepwise substitution by water on the timescale of the DNA interaction experiments, probably affording the species [RuCl(OH ₂ )(η ⁶ -p-cymene)(PRPh ₂ )] ²⁺ and [Ru(OH)(OH ₂ )(η ⁶ -p-cymene)(PRPh ₂ )] ²⁺ (where PRPh ₂ has R = [-(CH ₂ ) ₅ PPh ₂ -Fe(C ₅ H ₅ )(CO) ₂ ] ⁺ ). One interpretation of the combined DNA-interaction and kinetic data is that the mono(aqua) complex may interact with dsDNA through nucleobase coordination. Heterodinuclear 10 reacts with glutathione (GSH) to form stable mono- and bis(thiolate) adducts, 10-SG and 10-SG ₂ , with no evidence of metal ion reduction (k ₁ = 1.07 ± 0.17 × 10 ^-1 min ^-1 and k ₂ = 6.04 ± 0.59 × 10 ^-3 min ^-1 at 37 °C). This work highlights the synergistic effect of the Fe ²⁺ /Ru ²⁺ centres on both the cytotoxicity and biomolecular interactions of the present heterodinuclear complexes.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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