Organoruthenium Complexes with Benzo-Fused Pyrithiones Overcome Platinum Resistance in Ovarian Cancer Cells

Abstract

Drug resistance to existing anticancer agents is a growing clinical concern, with many first line treatments showing poor efficacy in treatment plans of some cancers. Resistance to platinum agents, such as cisplatin, is particularly prevalent in the treatment of ovarian cancer, one of the most common cancers amongst women in the developing world. Therefore, there is an urgent need to develop next generation of anticancer agents which can overcome resistance to existing therapies. We report a new series of organoruthenium(II) complexes bearing structurally modified pyrithione ligands with extended aromatic scaffold, which overcome platinum and adriamycin resistance in human ovarian cancer cells. The mechanism of action of such complexes appears to be unique from that of cisplatin, involving G1 cell cycle arrest without generation of cellular ROS, as is typically associated with similar ruthenium complexes. The complexes inhibit the enzyme thioredoxin reductase (TrxR) in a model system and reduce cell motility towards wound healing. Importantly, this work highlights further development in our understanding of the multi-targeting mechanism of action exhibited by transition metal complexes.

Comparison of Solution Chemical Properties and Biological Activity of Ruthenium Complexes of Selected β-Diketone, 8-Hydroxyquinoline and Pyrithione Ligands

“…In contrast, for PTA complex 4 with pyrithione ligand with an extended aromaticity it was recently reported to lose the activity once chlorido co-ligand in complex 3 is replaced by PTA [21]. Herein, complex 1 was the most active among the tested compounds; although the benzo-fused analogue complex 3 also shows similar cytotoxicity with a somewhat better selectivity index (i.e., higher ratio of IC 50 (MRC-5)/IC 50 (Colo 205 or 320)), and both being more selective than cisplatin.…”

“…In addition, another study was conducted where chlorido complex 3 and PTA complex 4 with HiQT ligand were screened on an array of cancer cell lines including cisplatin-and adriamycin-resistant strains. Increased lipophilicity of complex 3 resulting from the extension of the aromatic scaffold of the HiQT ligand is reflected in even lower IC 50 values on a similar panel of cancer cell lines, while complex 4 was surprisingly inactive at concentrations up to 50 µM [21]. Complex 5 was also reported to be cytotoxic against a series of human cancer cells and induced caspasedependent cell death in leukemia cells [17].…”

“…Complexes 1-5 and 7-8 were prepared according to published procedures [11,[15][16][17][18][19][20][21]. Namely, the neutral chlorido complexes 1, 3, 5 and 7 were prepared by the reaction of the corresponding ligand with half-equivalent of dimeric ruthenium precursor [Ru(η 6p-cymene)(µ-Cl) 2 ] 2 in the presence of sodium methoxide.…”

“…The PTA-containing complexes 2, 4, 6 and 8 were synthesized from the corresponding chlorido compounds using AgPF 6 /NH 4 PF 6 to remove the chloride ion and upon the addition of PTA phosphine ligand positively charged complexes were obtained as PF 6 − salts. Solid state structures 1-3, 5 and 7-8 were characterized by single crystal X-ray crystallography [11,[15][16][17][18][20][21][22][23]. The aromatic p-cymene is π-bounded to the metal ion, and the remaining three coordination sites are occupied by the deprotonated bidentate ligand and the chlorido or PTA co-ligand.…”

“…Either chloride ion or PTA were applied as co-ligands. Synthesis and cytotoxic activity of complexes 1-5 and 7-8 were reported in our previous works [15][16][17][18][19][20][21]. Additionally, complex 6 was newly prepared to perform a comparative study on cytotoxic, antibacterial (including antichlamydia) and antiviral activity of complexes in relation to their solution stability and reactivity.…”