TY - JOUR
T1 - Mechanistic studies on two dinuclear organogold(iii) compounds showing appreciable antiproliferative properties and a high redox stability
AU - Gabbiani, Chiara
AU - Casini, Angela
AU - Kelter, Gerhard
AU - Cocco, Fabio
AU - Cinellu, Maria Agostina
AU - Fiebig, Heinz Herbert
AU - Messori, Luigi
PY - 2011/12
Y1 - 2011/12
N2 - Two dinuclear oxo-bridged organogold(iii) compounds, namely [(N,N,C) 2Au 2(μ-O)][PF 6] 2 (with N,N,CH = 6-(1-methylbenzyl)-2,2′-bipyridine, Au 2O1; or 6-(1,1-dimethylbenzyl)-2,2′-bipyridine, Au 2O2), were previously prepared and characterised. Their solution chemistry under physiological-like conditions has been investigated here as well as their in vitro antiproliferative properties. Notably, these compounds reveal a marked redox stability even in the presence of effective biological reductants such as ascorbic acid and glutathione. The two dinuclear gold(iii) compounds were evaluated for cytotoxic actions against a representative panel of 12 human tumor cell lines, in comparison to respective mononuclear parent compounds [(N,N,C)AuOH][PF 6], and appreciable biological activity could be highlighted. The reactions of Au 2O1 and Au 2O2 with a few model proteins were studied and the ability to form metallodrug-protein adducts monitored through ESI MS methods. Typical adducts were identified where the protein is associated to monometallic gold fragments; in these adducts gold remains in the oxidation state +3 and conserves its organic ligand. A direct comparison of the biological profiles of these binuclear organogold(iii) compounds with those previously reported for a series of dinuclear oxo-bridged complexes [(N,N) 2Au 2(μ-O) 2][PF 6] 2 (N,N = 6(6′)-substituted 2,2′-bipyridines) named Auoxo's was carried out. It emerges that the greater cytotoxicity of the latter is mainly due to the greater oxidising power of their gold(iii) centres and to propensity to generate gold(i) species; in contrast, the here described bimetallic organogold(iii) complexes manifest a far higher redox stability in the biological milieu coupled to lower, but still significant, antiproliferative properties. Different molecular mechanisms are thus hypothesised for these two classes of dinuclear gold(iii) agents.
AB - Two dinuclear oxo-bridged organogold(iii) compounds, namely [(N,N,C) 2Au 2(μ-O)][PF 6] 2 (with N,N,CH = 6-(1-methylbenzyl)-2,2′-bipyridine, Au 2O1; or 6-(1,1-dimethylbenzyl)-2,2′-bipyridine, Au 2O2), were previously prepared and characterised. Their solution chemistry under physiological-like conditions has been investigated here as well as their in vitro antiproliferative properties. Notably, these compounds reveal a marked redox stability even in the presence of effective biological reductants such as ascorbic acid and glutathione. The two dinuclear gold(iii) compounds were evaluated for cytotoxic actions against a representative panel of 12 human tumor cell lines, in comparison to respective mononuclear parent compounds [(N,N,C)AuOH][PF 6], and appreciable biological activity could be highlighted. The reactions of Au 2O1 and Au 2O2 with a few model proteins were studied and the ability to form metallodrug-protein adducts monitored through ESI MS methods. Typical adducts were identified where the protein is associated to monometallic gold fragments; in these adducts gold remains in the oxidation state +3 and conserves its organic ligand. A direct comparison of the biological profiles of these binuclear organogold(iii) compounds with those previously reported for a series of dinuclear oxo-bridged complexes [(N,N) 2Au 2(μ-O) 2][PF 6] 2 (N,N = 6(6′)-substituted 2,2′-bipyridines) named Auoxo's was carried out. It emerges that the greater cytotoxicity of the latter is mainly due to the greater oxidising power of their gold(iii) centres and to propensity to generate gold(i) species; in contrast, the here described bimetallic organogold(iii) complexes manifest a far higher redox stability in the biological milieu coupled to lower, but still significant, antiproliferative properties. Different molecular mechanisms are thus hypothesised for these two classes of dinuclear gold(iii) agents.
UR - http://www.scopus.com/inward/record.url?scp=82455186212&partnerID=8YFLogxK
U2 - 10.1039/c1mt00113b
DO - 10.1039/c1mt00113b
M3 - Article
C2 - 21887452
AN - SCOPUS:82455186212
SN - 1756-5901
VL - 3
SP - 1318
EP - 1323
JO - Metallomics
JF - Metallomics
IS - 12
ER -