From Pyrone to Thiopyrone Ligands−Rendering Maltol-Derived Ruthenium(II)−Arene Complexes That Are Anticancer Active in Vitro

Abstract

Ru(II)-arene complexes with pyrone-derived ligands are rendered active against cancer cells by replacement of the coordinated O,O donor with an S,O donor. The different stabilities of these systems may explain the observed influence of the donor atoms on the anticancer activity in vitro.Metal complexes are playing an important role in the treatment of cancer, and many promising compounds have been developed in recent years. 1-4 Ruthenium complexes have been shown to be among the most promising candidates for new metal-based anticancer drugs. Two of them, KP1019 and NAMI-A, are currently undergoing clinical trials. 2,5 Their low general toxicity might be explained by their modes of action, including protein binding and activation by reduction. [5][6][7] More recently, bioorganometallic chemistry has emerged as a new source of anticancer metallodrugs, with titanocene dichloride being the prototype agent of this compound class. 4,8,9 Furthermore, organometallic Ru(II) compounds that are stabilized in their þ2 oxidation state by coordination of an arene ligand have been investigated for their anticancer properties. These piano-stool complexes have been pioneered by the Dyson and Sadler groups, 10,11 who developed compounds with pta (1,3,5-triaza-7-phoshatricyclo[3.3.1.1]-decane) and en (ethylenediamine) ligands, respectively. 10 For the [(η 6 -arene)Ru II (X)(Y)] complexes, DNA base selectivity strongly depends on the character of the chelating ligand Yexchange of the neutral ethylenediamine by anionic acetylacetonate shifts the affinity from guanine to adenine. 12 In addition to en and pta complexes, maltol-derived mono-and polynuclear ruthenium and osmium complexes have been developed. [13][14][15] The linking of two pyridone moieties opened up new possibilities for tuning the in vitro anticancer activity and lipophilicity, and compounds with interduplex cross-linking capacity were obtained. 14,16-18 In the case of the mononuclear Ru(II) complexes, an increase in cytotoxic activity was achieved by derivatization of the pyrone ring with lipophilic aromatic substituents. 13 In order to study the Ru-ligand interaction and its effect on the in vitro anticancer activity, Ru(II)-cymene complexes (Scheme 1) with pyrones and their corresponding, more lipophilic thiopyrones as chelating agents were prepared. 15,19 Such (thio)pyrone systems have already found application in Scheme 1. Synthesis of the Complexes 2a-d Jakupec, M. A.; Kynast, B.; Zorbas, H.; Keppler, B. K. J. Inorg. Biochem. 2006, 100, 891-904. (6) Groessl, M.; Reisner, E.; Hartinger, C. G.; Eichinger, R.; Semenova, O.; Timerbaev, A. R.; Jakupec, M. A.; Arion, V. B.; Keppler, B. K. Melchart, M.; Habtemariam, A.; Sadler, P. J. Chem. Commun. 2005, 4764-4776. (12) Fernandez, R.; Melchart, M.; Habtemariam, A.; Parsons, S.; Sadler, P. J. Chem. Eur. J. 2004, 10, 5173-5179.(13) Peacock, A. F. A.; Melchart, M.; Deeth, R. J.; Habtemariam, A.; Parsons, S.; Sadler, P. J. Chem. Eur. J. 2007, 13, 2601-2613. (14) Mendoza-Ferri, M. G.; Hartinger, C. G.; Eichinger, R. E.; Stoly...

Thiophenolato-bridged dinuclear arene ruthenium complexes: a new family of highly cytotoxic anticancer agents

“…27 In accordance with the electron count, the Ru-Ru distances (3.3576(5) and 3.3481(6)Å) are clearly outside of the range for a metal-metal single bond (2.28-2.95Å). 24 The three phenyl groups are not in the plane formed by the three sulfur atoms.…”

Antitumor pentamethylcyclopentadienyl rhodium complexes of maltol and allomaltol: Synthesis, solution speciation and bioactivity

“…The α-proton next to the carbonyl group of the pyrone ring was shifted to higher fields upon coordination of the metal ion, whereas the signal assigned to the β-proton next to the ether functionality of the backbone was found slightly low-field shifted compared to the free ligands (Figs. S1 and S2), which is comparable to the analogues Ru II complexes [39].…”

Solution equilibria of anticancer ruthenium(II)-(η6-p-cymene)-hydroxy(thio)pyr(id)one complexes: Impact of sulfur vs. oxygen donor systems on the speciation and bioactivity

“…The C-S bond for the chelating ligand was found at 1.70 Å, while the second monodentately bound thiomaltol ligand featured a slightly longer C-S distance at 1.74 Å. In related molecular structures of Ru II (arene) complexes, similar values were found for C-S bond lengths [21,42,43]. 1 H NMR spectra were recorded at various metal-to-ligand ratios at pH 9.0 and the total concentration of the hydroxythiopyrone ligands was kept constant (Figs.…”

“…The Ru II -S distances were at 2.41 and 2.46 Å for the bidentately-and monodentately-bound thiomaltolato ligands. This is slightly longer than found for Ru II -S bonds as determined in single crystal X-ray diffraction analyses [21,42,43]. The C-S bond for the chelating ligand was found at 1.70 Å, while the second monodentately bound thiomaltol ligand featured a slightly longer C-S distance at 1.74 Å.…”