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

Abstract

A series of ruthenium and iridium complexes have been synthesised and characterised with 20 novel crystal structures discussed. The library of -ketoiminato complexes has been shown to be active against MCF-7 (human breast carcinoma), HT-29 (human colon carcinoma), A2780 (human ovarian carcinoma) and A2780cis (cisplatin resistant human ovarian carcinoma) cell lines, with selected complexes being more than three times as active as cisplatin against the A2780cis cell line. Complexes have also been shown to be highly active under hypoxic conditions, with the activities of some complexes increasing with a decrease in O2 concentration. The enzyme thioredoxin reductase is over-expressed in cancer cells and complexes reported herein have the advantage of inhibiting this enzyme, with IC50 values measured in the nanomolar range. The anti-cancer activity of these complexes was further investigated to determine whether activity is due to effects on cellular growth or cell survival. The complexes were found to induce significant cancer cell death by apoptosis with levels induced correlating closely with activity in chemosensitivity studies. As a possible cause of cell death, the ability of the complexes to induce damage to cellular DNA was also assessed. The complexes failed to induce double strand DNA break or DNA crosslinking but induced significant levels of single DNA strand breaks indicating a different mechanism of action to cisplatin.

The development of anticancer ruthenium(ii) complexes: from single molecule compounds to nanomaterials

“…Ru(II) complexes with N,O -ligands were synthesized by Lord et al . 159 Most of the complexes were cytotoxic effect in HT-29 and MCF-7 cell lines, with significantly greater efficacy in A2780 and A2780cisR cells. In addition, the complexes were also cytotoxic to the hypoxic HT-29 cells.…”

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

“…24 We have previously reported a range of iridium picolinamide complexes that inhibit Trx-R, with IC 50 values in the nanomolar range. 19,25 This prompted us to investigate whether these novel complexes 2b, 2c, 2d, 3a and 3b reported here are also able to inhibit Trx-R activity. Significantly, all the active rhodium and iridium functionalised Cp ‡ dimers were found to be potent Trx-R inhibitors with IC 50 values in the nanomolar or low micromolar range (Table 3 and Figure S1).…”

“…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).…”

Bis‐picolinamide Ruthenium(III) Dihalide Complexes: Dichloride‐to‐Diiodide Exchange Generates Single trans Isomers with High Potency and Cancer Cell Selectivity

“…[41,42] More recently,G lazer and co-workers have compared the activities of cis-[Ru(bpy) 2 Cl 2 ]( bpy = 2,2'-bipyridine) with trans-[Ru(qpy)Cl 2 ]( qpy = 2,2':6',2'':6'',2'''-quaterpyridine), finding the trans isomer to be 7-10 times more active than the cis isomer. [43] This propensityf or the formation of different isomersi so ne of the reasonst hat there has been much effort dedicated to the synthesis and development of transition-metal-based candidates that are based on the molecular architectures associatedw ithM -arene, [44][45][46][47][48][49][50][51] MCp* [47,[52][53][54][55][56][57] and ferrocened erivatives. [58,59] The complexation of ruthenium to picolinamidel igandsi so f interestb ecause of its relevance to previously reported metalion peptide chemistry and the possibility of different ligand bindingm odes that can potentially alter the biological activity of the complexes.…”