The contrasting chemical reactivity of potent isoelectronic iminopyridine and azopyridine osmium(ii) arene anticancer complexes

Abstract

A wide variety of steric and electronic features can be incorporated into transition metal coordination complexes, offering the prospect of rationally-designed therapeutic agents with novel mechanisms of action. Here we compare the chemical reactivity and anticancer activity of organometallic Os II complexes [Os(h 6 -arene)(XY)Z]PF 6 where arene ¼ p-cymene or biphenyl, XY ¼ N,N 0 -chelated phenyliminopyridine or phenylazopyridine derivatives, and Z ¼ Cl or I. The X-ray crystal structure of [Os(h 6 -p-cym)(Impy-OHLike the azopyridine complexes we reported recently (Dalton Trans., 2011, 40, 10553-10562), some iminopyridine complexes are also potently active towards cancer cells (nanomolar IC 50 values). However we show that, unlike the azopyridine complexes, the iminopyridine complexes can undergo aquation, bind to the nucleobase guanine, and oxidize coenzyme nicotine adenine dinucleotide (NADH). We report the first detection of an Os-hydride adduct in aqueous solution by 1 H NMR (À4.2 ppm). Active iminopyridine complexes induced a dramatic increase in the levels of reactive oxygen species (ROS) in A549 lung cancer cells. The anticancer activity may therefore involve interference in the redox signalling pathways in cancer cells by a novel mechanism.

The Contrasting Activity of Iodido versus Chlorido Ruthenium and Osmium Arene Azo- and Imino-pyridine Anticancer Complexes: Control of Cell Selectivity, Cross-Resistance, p53 Dependence, and Apoptosis Pathway

“…Complex 3 aquates to an extent of 55% in the same time, while the iodido complex 4 is inert and does not form an aqua complex under these conditions. 21 Aquation of the osmium analogues was also studied; chlorido complex 5 aquates 50% after 24 h, and complex 6 is fully converted to the aqua species in the same time 22 (Supporting Information Table S1). However, this aquation reaction was totally inhibited by the presence of chloride ions.…”

“…16,17 Such complexes can often undergo activation by aquation, the loss/replacement of the monodentate ligand 16 and subsequent binding to DNA nucleobases such as guanine and adenine 18 or even conjugation to glutathione followed by oxidation to the sulfenate and then DNA binding. 19,20 Complexes 22 [Os(η 6 -p-cym)(p-Impy−NMe 2 )I]-PF 6 (6) 22 were obtained as previously reported. These complexes contain either iminopyridine (1, 2, 5, 6) or isoelectronic azopyridine (3,4) as the N,N-chelator, and chloride (1,3,5) ) show that 2 mM solutions of complexes 1 and 2 in water aquate (replacement of halide by water) to a similar extent over 24 h, 66% and 63%, respectively.…”

Potent organo-osmium compound shifts metabolism in epithelial ovarian cancer cells

“…1A) exhibits higher in vitro antiproliferative activity in A2780 ovarian cancer cells, compared with cisplatin, and is equipotent in cisplatinresistant EOC cells (13,14). It is also highly active (EC 50 : 0.85-2.14 μM) in patient-derived high-grade serous ovarian cancer cells PE01 and PE04 (SI Appendix, SI Materials and Methods and Fig.…”

Bidentate Ligands on Osmium(VI) Nitrido Complexes Control Intracellular Targeting and Cell Death Pathways

“…7 Nevertheless, several half-sandwich “piano-stool” osmium(II) arene complexes have emerged with promising in vitro activity and no cisplatin cross-resistance. 8 More recently, DNA-targeting osmium(VI) nitrido compounds with tridendate Schiff bases 9 and monodenate azole heterocycle ligands 10 have displayed encouraging in vitro and in vivo properties. Here we report the anti-cancer properties of osmium(VI) nitrido compounds bearing bidentate ligands in which small changes to the ligand periphery evoke completely different cellular responses.…”