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

M. Odachowski, R. Neven, G. Perversi, D. Romano, C.A. Slabber, M. Hadiji, M. Honing, O.Q. Munro*, Y.D. Zhao, B. Blom*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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 [Fe2+, Ru2+] com-plexes to delineate how ligand structural variations modulate compound cytotoxicity. Specifically, Fe(II) complexes of the type [(eta(5)-C5H5)Fe(CO)(2)(kappa(1)-PPh2(CH2)(n)PPh2)]{PF6} (n = 1-5), compounds 1-5, and heterodinuclear [Fe2+, Ru2+] complexes, [(eta(5)-C5H5)Fe(CO)(2)(mu-PPh2(CH2)nPPh(2)))(eta(6)-p-cymene)RuCl2]{PF6} (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 IC50 values ranging from 2.3 +/- 0.5 mu M to 9.0 +/- 1.4 mu M. For 7-10, the cytotoxicity increased with increasing Fe center dot center dot center dot 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(OH2)(eta(6)-p-cymene)(PRPh2)](2+) and [Ru(OH)(OH2)(eta(6)-p-cymene)(PRPh2)](2+) (where PRPh2 has R = [-(CH2)(5)PPh2-Fe(C5H5)(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 x 10(-1) min(-1) and k(2) = 6.04 +/- 0.59 x 10-3 min(-1) at 37 degrees C). This work highlights the synergistic effect of the Fe2+/Ru2+ centres on both the cytotoxicity and biomolecular interactions of the present heterodinuclear complexes.
Original languageEnglish
Article number112156
Number of pages20
JournalJournal of Inorganic Biochemistry
Volume242
DOIs
Publication statusPublished - 1 May 2023

Keywords

  • Ruthenium
  • Metallodrug
  • Cytotoxic
  • DNA-binding
  • Glutathione coordination
  • RUTHENIUM POLYPYRIDYL COMPLEXES
  • HALF-SANDWICH COMPLEXES
  • COMPOUND RAPTA-C
  • IN-VITRO
  • ORGANOMETALLIC RUTHENIUM(II)
  • ARENE COMPLEXES
  • ANTICANCER COMPLEXES
  • BREAST-CANCER
  • ANTITUMOR METALLODRUGS
  • LIGANDS SYNTHESIS

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