Gold(III) dithiocarbamate derivatives for the treatment of cancer: solution chemistry, DNA binding, and hemolytic properties.
Gold(III) compounds are emerging as a new class of metal complexes with outstanding cytotoxic properties and are presently being evaluated as potential antitumor agents. We report here on the solution and electrochemical properties, and the biological behavior of some gold(III) dithiocarbamate derivatives which have been recently proved to be one to 4 orders of magnitude more cytotoxic in vitro than the reference drug (cisplatin) and to be able to overcome to a large extent both intrinsic and acquired resistance to cisplatin itself. Their solution properties have been monitored in order to study their stability under physiological conditions; remarkably, they have shown to undergo complete hydrolysis within 1 h, the metal center remaining in the +3 oxidation state. Their DNA binding properties and ability in hemolyzing red blood cells have been also evaluated. These gold(III) complexes show high reactivity toward some biologically important isolated macromolecules, resulting in a dramatic inhibition of both DNA and RNA synthesis and inducing DNA lesions with a faster kinetics than cisplatin. Nevertheless, they also induce a strong and fast hemolytic effect (compared to cisplatin), suggesting that intracellular DNA might not represent their primary or exclusive biological target.
Ronconi
Luca
L
Department of Chemical Sciences, University of Padova, via Marzolo 1, 35131 Padova, Italy.
Marzano
Christine
C
Zanello
Piero
P
Corsini
Maddalena
M
Miolo
Giorgia
G
Maccà
Carlo
C
Trevisan
Andrea
A
Fregona
Dolores
D
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002417:Cattle; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D003432:Cross-Linking Reagents / Q000737:chemistry; D004247:DNA / Q000737:chemistry*; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006461:Hemolysis; D006868:Hydrolysis; D066298:In Vitro Techniques; D007700:Kinetics; D051379:Mice; D050607:Organogold Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012996:Solutions; D013329:Structure-Activity Relationship; D013859:Thiocarbamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013936:Thymidine / Q000378:metabolism; D014316:Tritium; D014529:Uridine / Q000378:metabolism
D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D050607:Organogold Compounds; D012996:Solutions; D013859:Thiocarbamates; D014316:Tritium; D004247:DNA; C427203:calf thymus DNA; D002945:Cisplatin; D013936:Thymidine; D014529:Uridine