Structure−Activity Relationships for Cytotoxic Ruthenium(II) Arene Complexes Containing N,N-, N,O-, and O,O-Chelating Ligands

Abstract

We report structure-activity relationships for organometallic RuII complexes of the type [(eta6-arene)Ru(XY)Cl]Z, where XY is an N,N- (diamine), N,O- (e.g., amino acidate), or O,O- (e.g., beta-diketonate) chelating ligand, the arene ranges from benzene derivatives to fused polycyclic hydrocarbons, and Z is usually PF6. The X-ray structures of 13 complexes are reported. All have the characteristic "piano-stool" geometry. The complexes most active toward A2780 human ovarian cancer cells contained XY=ethylenediamine (en) and extended polycyclic arenes. Complexes with polar substituents on the arene or XY=bipyridyl derivatives exhibited reduced activity. The activity of the O,O-chelated complexes depended strongly on the substituents and on the arene. For arene=p-cymene, XY=amino acidate complexes were inactive. Complexes were not cross-resistant with cisplatin, and cross-resistance to Adriamycin was circumvented by replacing XY=en with 1,2-phenylenediamine. Some complexes were also active against colon, pancreatic, and lung cancer cells.

Comparative solution equilibrium studies on pentamethylcyclopentadienyl rhodium complexes of 2,2ʹ-bipyridine and ethylenediamine and their interaction with human serum albumin

“…However, no comparable H 2 O/Cl -exchange constants for RhCp* complexes are published in the literature to the best of our knowledge, similar findings were found for IrCp* complexes of bpy, en and phen [57], and for some Os and Ru arene complexes as well [49,58]. Fig.…”

Hypoxia-Sensitive Metal β-Ketoiminato Complexes Showing Induced Single-Strand DNA Breaks and Cancer Cell Death by Apoptosis

“…Most importantly ruthenium is thought to have slow in vivo ligand exchange and higher selectively towards cancer cells leading to lower toxicity. [1][2][3][4] The discovery of organometallic ruthenium complexes first began with the library of [( 6 -arene)Ru(II)(en)X] + (X = halide, en = ethylenediamine) complexes synthesised by Sheldrick et al [5][6][7] The effect of the ligand was later explored by Sadler et al substituting the neutral (N,N) ethylenediamine ligand for an anionic (O,O) -diketonato ligand, showing a significant increase in cytoxicity of the complexes. 8 In collaboration with Sadler, McGowan et al first synthesised picolinamide Ru(II) and Os(II) arene complexes due to their relevence to previously reported metal ion-peptide chemistry [9][10][11] and the possibility of different binding modes, through either a monoanionic (N,N) or a neutral (N,O) form.…”

Comparative equilibrium and structural studies of new pentamethylcyclopentadienyl rhodium complexes bearing (O,N) donor bidentate ligands

“…One possible reason for poor anticancer activities of compounds 1-3 could be an impeded aquation due to the exceptionally high affinity of the complexes for chloride ions. This correlation has already been pointed out for related Ru(II), Os(II) and Ir(III) complexes [34][35][36]. However, high chloride ion affinity may hinder not only the aquation of the complexes but also possible monodentate coordination of bio-ligands (such as proteins or DNA nucleobases).…”

“…It is a reasonable hypothesis that the increased chloride ion affinity of RhCp* complexes, just like in case of analogous Ir(III)-Cp* and some Ru(II)-arene compounds [34][35][36], may correlate with the poor in vitro anticancer activity. On the other hand several other physicochemical factors such as lipophilicity, redox and kinetic properties etc.…”