3 research outputs found
Impact of the Halogen Substitution Pattern on the Biological Activity of Organoruthenium 8âHydroxyquinoline Anticancer Agents
8-Hydroxyquinoline and its derivatives
have a broad variety of
pharmacological properties, which make them an ideal bioactive building
block in the development of metal-based anticancer drugs. In this
account we aimed to rationalize the antiproliferative efficacy of
organoruthenium compounds featuring 8-hydroxyquinoline-derived ligands
and to elucidate structural determinants by using biological assays
and bioanalytical methods. By systematically varying the halide substitution
pattern at the 5- and 7-positions of the 8-hydroxyquinoline ligand,
as well as the halido leaving group, a series of 5,7-dihalido-8-hydroxyquinoline
Ru<sup>II</sup>(η<sup>6</sup>-<i>p</i>-cymene) complexes
were obtained. Studies on their cytotoxic activity revealed the minor
impact of the substitution pattern (with the exception of complexes
of 8-hydroxyquinoline) on their activity. Notably, the cellular accumulation
showed no correlation with the cytotoxic activity, while the nature
of the halido leaving group only had a significant influence in the
case of the 8-hydroxyquinoline organoruthenium compounds. However,
the compounds were shown to be very stable under a wide variety of
pH conditions, making them possible candidates for further development
as orally active anticancer agents
Impact of the Halogen Substitution Pattern on the Biological Activity of Organoruthenium 8âHydroxyquinoline Anticancer Agents
8-Hydroxyquinoline and its derivatives
have a broad variety of
pharmacological properties, which make them an ideal bioactive building
block in the development of metal-based anticancer drugs. In this
account we aimed to rationalize the antiproliferative efficacy of
organoruthenium compounds featuring 8-hydroxyquinoline-derived ligands
and to elucidate structural determinants by using biological assays
and bioanalytical methods. By systematically varying the halide substitution
pattern at the 5- and 7-positions of the 8-hydroxyquinoline ligand,
as well as the halido leaving group, a series of 5,7-dihalido-8-hydroxyquinoline
Ru<sup>II</sup>(η<sup>6</sup>-<i>p</i>-cymene) complexes
were obtained. Studies on their cytotoxic activity revealed the minor
impact of the substitution pattern (with the exception of complexes
of 8-hydroxyquinoline) on their activity. Notably, the cellular accumulation
showed no correlation with the cytotoxic activity, while the nature
of the halido leaving group only had a significant influence in the
case of the 8-hydroxyquinoline organoruthenium compounds. However,
the compounds were shown to be very stable under a wide variety of
pH conditions, making them possible candidates for further development
as orally active anticancer agents
From Catalysis to Cancer: Toward StructureâActivity Relationships for Benzimidazol-2-ylidene-Derived <i>N</i>âHeterocyclic-Carbene Complexes as Anticancer Agents
The promise of the metalÂ(arene) structure
as an anticancer pharmacophore has prompted intensive exploration
of this chemical space. While <i>N</i>-heterocyclic carbene
(NHC) ligands are widely used in catalysis, they have only recently
been considered in metal complexes for medicinal applications. Surprisingly,
a comparatively small number of studies have been reported in which
the NHC ligand was coordinated to the Ru<sup>II</sup>(arene) pharmacophore
and even less with an Os<sup>II</sup>(arene) pharmacophore. Here,
we present a systematic study in which we compared symmetrically substituted
methyl and benzyl derivatives with the nonsymmetric methyl/benzyl
analogues. Through variation of the metal center and the halido ligands,
an in-depth study was conducted on ligand exchange properties of these
complexes and their biomolecule binding, noting in particular the
stability of the MâC<sub>NHC</sub> bond. In addition, we demonstrated
the ability of the complexes to inhibit the selenoenzyme thioredoxin
reductase (TrxR), suggested as an important target for anticancer
metalâNHC complexes, and their cytotoxicity in human tumor
cells. It was found that the most potent TrxR inhibitor diiodidoÂ(1,3-dibenzylbenzimidazol-2-ylidene)Â(η<sup>6</sup>-p-cymene)ÂrutheniumÂ(II) <b>1b</b><sup><b>I</b></sup> was also the most cytotoxic compound of the series, with the
antiproliferative effects in general in the low to middle micromolar
range. However, since there was no clear correlation between TrxR
inhibition and antiproliferative potency across the compounds, TrxR
inhibition is unlikely to be the main mode of action for the compound
type and other target interactions must be considered in future