title: Synthesis and characterization of azolate gold(I) phosphane complexes as thioredoxin reductase inhibiting antitumor agents.
abstract: Following an increasing interest in the gold drug therapy field, nine new neutral azolate gold(I) phosphane compounds have been synthesized and tested as anticancer agents. The azolate ligands used in this study are pyrazolates and imidazolates substituted with deactivating groups such as trifluoromethyl, nitro or chloride moieties, whereas the phosphane co-ligand is the triphenylphosphane or the more hydrophilic TPA (TPA = 1,3,5-triazaphosphaadamantane). The studied gold(I) complexes are: (3,5-bis-trifluoromethyl-1H-pyrazolate-1-yl)-triphenylphosphane-gold(I) (1), (3,5-dinitro-1H-pyrazolate-1-yl)-triphenylphosphane-gold(I) (2), (4-nitro-1H-pyrazolate-1-yl)-triphenylphosphane-gold(I) (5), (4,5-dichloro-1H-imidazolate-1-yl)-triphenylphosphane-gold(I) (7), with the related TPA complexes (3), (4), (6) and (8) and (1-benzyl-4,5-di-chloro-2H-imidazolate-2-yl)-triphenylphosphane-gold(I) (9). The presence of deactivating groups on the azole rings improves the solubility of these complexes in polar media. Compounds 1-8 contain the N-Au-P environment, whilst compound 9 is the only one to contain a C-Au-P environment. Crystal structures for compounds 1 and 2 have been obtained and discussed. Interestingly, the newly synthesized gold(I) compounds were found to possess a pronounced cytotoxic activity on several human cancer cells, some of which were endowed with cis-platin or multidrug resistance. In particular, among azolate gold(I) complexes, 1 and 2 proved to be the most promising derivatives eliciting an antiproliferative effect up to 70 times higher than cis-platin. Mechanistic experiments indicated that the inhibition of thioredoxin reductase (TrxR) might be involved in the pharmacodynamic behavior of these gold species.
authors.affiliation: School of Science and Technology, Chemistry Division, University of Camerino, via S. Agostino, 1, 62032 Camerino, Italy. rossana.galassi@unicam.it
authors.forename: Rossana
authors.initials: R
authors.lastname: Galassi
authors.forename: Alfredo
authors.initials: A
authors.lastname: Burini
authors.forename: Simone
authors.initials: S
authors.lastname: Ricci
authors.forename: Maura
authors.initials: M
authors.lastname: Pellei
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Rigobello
authors.forename: Anna
authors.initials: A
authors.lastname: Citta
authors.forename: Alessandro
authors.initials: A
authors.lastname: Dolmella
authors.forename: Valentina
authors.initials: V
authors.lastname: Gandin
authors.forename: Cristina
authors.initials: C
authors.lastname: Marzano
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic / Q000379:methods*; D018432:Drug Resistance, Multiple / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005980:Glutathione Reductase / Q000037:antagonists & inhibitors; D006801:Humans; D050607:Organogold Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010720:Phosphines / Q000737:chemistry*; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D050607:Organogold Compounds; D010720:Phosphines; D005980:Glutathione Reductase; D013880:Thioredoxin-Disulfide Reductase; C044646:phosphine