Is the Reactivity of M(II)−Arene Complexes of 3-Hydroxy-2(1H)-pyridones to Biomolecules the Anticancer Activity Determining Parameter?

Abstract

Hydroxypyr(id)ones are versatile ligands for the synthesis of organometallic anticancer agents, equipping them with fine-tunable pharmacological properties. Herein, we report on the preparation, mode of action, and in vitro anticancer activity of Ru(II)- and Os(II)-arene complexes with alkoxycarbonylmethyl-3-hydroxy-2-pyridone ligands. The hydrolysis and binding to amino acids proceed quickly, as characterized by NMR spectroscopy and ESI mass spectrometry. However, the reaction with amino acids causes cleavage of the pyridone ligands from the metal center because the amino acids act as multidentate ligands. A similar behavior was also observed during the reactions with the model proteins ubiquitin and cytochrome c, yielding mainly [protein + M(eta(6)-p-cymene)] adducts (M = Ru, Os). Notably the ligand cleavage of the Os derivative was significantly slower than of its Ru analogue, which could explain its higher activity in in vitro anticancer assays. Furthermore, the reaction of the compounds to 5'-GMP was characterized and coordination to the N7 of the guanine moiety was demonstrated by (1)H NMR spectroscopy and X-ray diffraction analysis. CDK2/Cyclin A protein kinase inhibition studies revealed potent activity of the Ru and Os complexes.

Solution equilibrium studies of anticancer ruthenium(II)-η6-p-cymene complexes of pyridinecarboxylic acids

“…1 and S3). The slow dissociation of the complex [ML] + was similar to that of hydroxypyridone complexes [49], for which however to a significant degree formation of the hydroxido-bridged dimer [M 2 H −3 ] + was detected. This was observed for Ru(II)(η 6 -p-cymene) complexes of hydroxypyrones such as ethyl maltol [37] and maltol [49] at pH > 8.8 and already at pH 7.4, respectively in the mM concentration range in chloride-free medium.…”

“…In order to compare the differences in speciation and thus in the stability of the complexes order of biological activity [28,30,36,[47][48][49]. …”

Novel microwave synthesis of half‐sandwich [(η6‐C6H6)Ru] complexes and an evaluation of the biological activity and biochemical reactivity

“…This idea is not that uncommon as other workers have made similar observations. [29,30] Electronic absorption measurements also show that the complexes can interact with these proteins. The main peaks of the complexes show significant hypochromism when they are incubated with the proteins and a small but discernible blue shift (2 nm) is seen for 2 ( Fig.…”

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 substitution of original chelating ligands by endogenous biomolecules has a major impact on the integrity of the complexes and their presence in the biologically active form fundamentally depends on the thermodynamic stability and kinetic inertness/lability. Only little information is available in the literature about the solution speciation of ruthenium(II)- 6 -arene complexes: on the formation of complexes with bidentate (O,O) ligands was studied [16] and pK a values of the coordinated water molecule in [Ru II ( 6 -p-cymene)(XY)(H 2 O)] species were determined for several XY bidentate ligands [5,[17][18][19]. Complexes of hydroxypyrones (such as the well-known 3-hydroxy-2-methyl-4H-pyran-4-one (maltol)) show only moderate cytotoxicity on various cancer cell lines as compared with the more active (O,S) type complexes of hydroxythiopyrones [5].…”