Cytotoxicity and cellular impact of dinuclear organoiridium DNA intercalators and nucleases with long rigid bridging ligands

Abstract

The DNA binding modes and cleavage properties of novel dinuclear Ir(III) polypyridyl (pp) complexes [{(η(5)-C(5)Me(5))Ir(pp)}(2)(μ-B)](CF(3)SO(3))(4) depend on the lengths of their rigid bridging dipyridinyl ligands B. Mono-intercalation and strong DNA cleavage properties were observed for the dipyrido[2,3-a:2',3'-c]phenazine (dppz) complexes 1 (B = 4-[(E)-2-(4-pyridinyl)ethenyl]pyridine) and 3 (B = 4-(2-pyridin-4-ylethynyl)pyridine), whose intracationic Ir···Ir' distances are about 13.1 and 13.3 Å, respectively. In contrast, UV/Vis and CD spectra were in accordance with a stable intertwined bis-intercalation mode for pairs of cations of 5 (B = 1,4-di(2-pyridin-4-ylethynyl)benzene), whose much longer Ir···Ir' distance of 20.6 Å allows a stack of five aromatic chromophores to be sandwiched between its effectively parallel dppz ligands. Whereas both 1 and 3 cleaved DNA in the dark, complex 5 exhibited only photoinduced nuclease activity. A significantly higher antiproliferative activity towards MCF-7 breast carcinoma cells was observed for the nucleases 1 and 3, whose IC(50) values of 0.61 and 0.49 were much lower than that of 2.2 μM for bis-intercalator 5. Values of 3.8 μM, only slightly higher than that of 5, were recorded for the 5,6-dimethylphenanthroline complexes 4 and 6, whose bridging ligands are identical to those of 3 and 5, respectively. Marked antileukemic activity (IC(50) = 6-7 μM) associated with increased levels of reactive oxygen species and apoptosis induction was recorded for both 3 and 5 towards Jurkat cells at concentrations of 5 μM and above. Online studies with a sensor chip system indicated that 5 μM solutions of these complexes invoke a rapid and massive reduction in MCF-7 cell respiration.

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

“…Whereas RhCp* complexes formed with 2-picolinic acid (pic) [12] and 3-hydroxy(thio)pyrones derivatized by morpholine, piperidine or N-methylpyrazine moieties [13] exhibited only poor or no bioactivity. Promising in vitro antiproliferative activities have been reported for the RhCp* complexes of (N,N) polypyridyl (pp) ligands by Sheldrick et al [14][15][16][17] possessing IC 50 values in the low micromolar range. However, the RhCp* complexes of the simplest bidentate alkylamino and aromatic N-donor ligands, namely ethylenediamine (en) and 2,2'-bipyridine (bpy) did not show significant cytotoxicity (IC 50 >100 μM measured in MCF-7 and HT-29 cells) [17].…”

Antagonizing STAT3 Dimerization with a Rhodium(III) Complex

“…[15] Polypyridyl-containing iridium half-sandwich complexes have been demonstrated by the groups of Sadler and Sheldrick to bind to DNA through intercalative and/or covalent binding modes. [16] In contrast, Sheldrick and co-workers have found that a number of other polypyridyl-containing trichloro iridium and rhodium complexes surprisingly did not significantly interact with DNA. [17] To explore this issue further, we investigated the ability of the complexes 10-35, identified from the second round of screening, to interact with DNA by using fluorescence resonance energy transfer (FRET) melting experiments ( Figure S5 shows representative spectra for 12).…”

Increasing anti-cancer activity with longer tether lengths of group 9 Cp* complexes

“…16 Therefore, breaking up the rhodium and iridium dihalide Cp* dimers with different bidentate ligands led to the development of complexes which show high in vitro cytotoxic activity against tumour cell lines. [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] Where tested, studies have reported negligible activities of the starting dimers, i.e. [Cp*MCl 2 ] 2 (M = Rh or Ir) 16 (M = Rh or Ir).…”