Maltol‐Derived Ruthenium–Cymene Complexes with Tumor Inhibiting Properties: The Impact of Ligand–Metal Bond Stability on Anticancer Activity In Vitro

Abstract

Organometallic ruthenium-arene compounds bearing a maltol ligand have been shown to be nearly inactive in in vitro anticancer assays, presumably due to the formation of dimeric Ru(II) species in aqueous solutions. In an attempt to stabilize such complexes, [Ru(eta(6)-p-cymene)(XY)Cl] (XY=pyrones or thiopyrones) complexes with different substitution pattern of the (thio)pyrone ligands have been synthesized, their structures characterized spectroscopically, and their aquation behavior investigated as well as their tumor-inhibiting potency. The aquation behavior of pyrone systems with electron-donating substituents and of thiopyrone complexes was found to be significantly different from that of the maltol-type complex reported previously. However, the formation of the dimer can be excluded as the primary reason for the inactivity of the complex because some of the stable compounds are not active in cancer cell lines either. In contrast, studies of their reactivity towards amino acids demonstrate different reactivities of the pyrone and thiopyrone complexes, and the higher stability of the latter probably renders them active against human tumor cells.

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

“…These comprise picolinic acid, thiomaltol, thioallomaltol, etc. [26,[29][30][31][32][33][34][35]. The type of chelating ligands does not only have an influence on the biological properties but also impacts the stability of the complex formed by preventing hydrolysis of the Ru(II)( 6 -p-cymene) organometallic fragment.…”

“…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]. …”

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

“…In the last decade, numerous organometallic ruthenium(II)- 6 -arene complexes mainly with piano-stool structure were synthesized and tested in in vitro assays regarding their bioactivity. In these Ru II [5][6][7][8][9][10][11][12]. The chloride ligand acts a leaving group and its replacement by a water molecule facilitates the reaction with biological targets.…”

Platinum(II) and palladium(II) complexes with (N,N′) and (C,N,N′)− ligands derived from pyrazole as anticancer and antimalarial agents: Synthesis, characterization and in vitro activities

“…Cyclometallated complexes derived from N-donor ligands have attracted great interest during the last decade due to their properties and applications in a wide variety of fields [10,[20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] and compounds of this kind containing Pd(II), Pt(II), Ru(II), Ir(III) Rh(III) and Au have shown promising cytotoxic activities [10,20,[27][28][29][30][31][32][33][34][35][36]. Few cyclopalladated complexes derived from pyrazole are known [37][38][39][40][41] and, to the best of our knowledge, their cytotoxicity has only been reported once [41].…”