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Green light-induced apoptosis in cancer cells by a tetrapyridyl ruthenium prodrug offering two trans coordination sites.

ABSTRACT: In this work, two new photopharmacological ruthenium prodrugs are described that can be activated by green light. They are based on the tetrapyridyl biqbpy ligand (6,6'-bis[N-(isoquinolyl)-1-amino]-2,2'-bipyridine), which coordinates to the basal plane of the metal centre and leaves two trans coordination sites for the binding of monodentate sulphur ligands. Due to the distortion of the coordination sphere these trans ligands are photosubstituted by water upon green light irradiation. In vitro cytotoxicity data on A431 and A549 cancer cell lines shows an up to 22-fold increase in cytotoxicity after green light irradiation (520 nm, 75 J cm^-2), compared to the dark control. Optical microscopy cell imaging and flow cytometry indicate that the cancer cells die via apoptosis. Meanwhile, very low singlet oxygen quantum yields (?1-2%) and cell-free DNA binding studies conclude that light-induced cell death is not caused by a photodynamic effect, but instead by the changes induced in the coordination sphere of the metal by light, which modifies how the metal complexes bind to biomolecules.

SUBMITTER: van Rixel VHS

PROVIDER: S-EPMC6018302 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Green light-induced apoptosis in cancer cells by a tetrapyridyl ruthenium prodrug offering two trans coordination sites.

van Rixel V H S VHS Siewert B B Hopkins S L SL Askes S H C SHC Busemann A A Siegler M A MA Bonnet Sylvestre S

Chemical science 20160425 8

In this work, two new photopharmacological ruthenium prodrugs are described that can be activated by green light. They are based on the tetrapyridyl biqbpy ligand (6,6'-bis[N-(isoquinolyl)-1-amino]-2,2'-bipyridine), which coordinates to the basal plane of the metal centre and leaves two trans coordination sites for the binding of monodentate sulphur ligands. Due to the distortion of the coordination sphere these trans ligands are photosubstituted by water upon green light ir ...[more]

PMID: 30155140

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Project description:In this work, a pair of gold(III) complexes derived from the analogous tetrapyridyl ligands H2biqbpy1 and H2biqbpy2 was prepared: the rollover, bis-cyclometalated [Au(biqbpy1)Cl ([1]Cl) and its isomer [Au(biqbpy2)Cl ([2]Cl). In [1]+, two pyridyl rings coordinate to the metal via a Au-C bond (C∧N∧N∧C coordination) and the two noncoordinated amine bridges of the ligand remain protonated, while in [2]+ all four pyridyl rings of the ligand coordinate to the metal via a Au-N bond (N∧N∧N∧N coordination), but both amine bridges are deprotonated. As a result, both complexes are monocationic, which allowed comparison of the sole effect of cyclometalation on the chemistry, protein interaction, and anticancer properties of the gold(III) compounds. Due to their identical monocationic charge and similar molecular shape, both complexes [1]Cl and [2]Cl displaced reference radioligand [3H]dofetilide equally well from cell membranes expressing the Kv11.1 (hERG) potassium channel, and more so than the tetrapyridyl ligands H2biqbpy1 and H2biqbpy2. By contrast, cyclometalation rendered [1]Cl coordinatively stable in the presence of biological thiols, while [2]Cl was reduced by a millimolar concentration of glutathione into metastable Au(I) species releasing the free ligand H2biqbpy2 and TrxR-inhibiting Au+ ions. The redox stability of [1]Cl dramatically decreased its thioredoxin reductase (TrxR) inhibition properties, compared to [2]Cl. On the other hand, unlike [2]Cl, [1]Cl aggregated into nanoparticles in FCS-containing medium, which resulted in much more efficient gold cellular uptake. [1]Cl had much more selective anticancer properties than [2]Cl and cisplatin, as it was almost 10 times more cytotoxic to human cancer cells (A549, A431, A375, and MCF7) than to noncancerous cells (MRC5). Mechanistic studies highlight the strikingly different mode of action of the two compounds: while for [1]Cl high gold cellular uptake, nuclear DNA damage, and interaction with hERG may contribute to cell killing, for [2]Cl extracellular reduction released TrxR-inhibiting Au+ ions that were taken up in minute amounts in the cytosol, and a toxic tetrapyridyl ligand also capable of binding to hERG. These results demonstrate that bis-cyclometalation is an appealing method to improve the redox stability of Au(III) compounds and to develop gold-based cytotoxic compounds that do not rely on TrxR inhibition to kill cancer cells.

Dataset Information

Green light-induced apoptosis in cancer cells by a tetrapyridyl ruthenium prodrug offering two trans coordination sites.

Publications

Green light-induced apoptosis in cancer cells by a tetrapyridyl ruthenium prodrug offering two <i>trans</i> coordination sites.

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