title: Novel antitumor adamantane-azole gold(I) complexes as potential inhibitors of thioredoxin reductase.
abstract: Gold complexes that could act as antitumor agents have attracted great attention. Heterocyclic compounds and their metal complexes display a broad spectrum of pharmacological properties. The present study reports the preparation and characterization of four novel gold(I) complexes containing tertiary phosphine and new ligands 5-adamantyl-1,3-thiazolidine-2-thione, 3-methyladamantane-1,3,4-oxadiazole-2-thione. Spectroscopic data suggest that gold is coordinated to the exocyclic sulfur atom in all cases, as confirmed by X-ray crystallographic data obtained for complex (1) and supported by quantum-mechanical calculations. The cytotoxicity of the compounds has been evaluated in comparison to cisplatin and auranofin in three different tumor cell lines, colon cancer (CT26WT), metastatic skin melanoma (B16F10), mammary adenocarcinoma (4T1) and kidney normal cell (BHK-21). The gold complexes were more active than their respective free ligands and able to inhibit the thioredoxin reductase (TrxR) enzyme, even in the presence of albumin. Molecular modeling studies were carried out to understand the interaction between the compounds and the TrxR enzyme, considered as a potential target for new compounds in cancer treatment. The docking results show that the adamantane ring is essential to stabilize the ligand-enzyme complex prior the formation of covalent bond with gold center. The structure of the new gold compounds was established on the basis of spectroscopic data, DFT calculations and X-ray diffraction. TrxR inhibition was evaluated and the results correlated with the assays in tumor cells, suggesting the TrxR as possible target for these compounds.
authors: Departamento de Química, ICE, Universidade Federal de Juiz de Fora, Juiz De Fora, MG, 36036-900, Brazil.
authors: Adriana
authors: A
authors: Garcia
authors: Departamento de Química, ICE, Universidade Federal de Juiz de Fora, Juiz De Fora, MG, 36036-900, Brazil.
authors: Rafael Carvalhaes
authors: RC
authors: Machado
authors: Departamento de Química, ICE, Universidade Federal de Juiz de Fora, Juiz De Fora, MG, 36036-900, Brazil.
authors: Richard Michael
authors: RM
authors: Grazul
authors: Departamento de Farmacologia, ICB, Universidade Federal de Minas Gerais, Belo Horizonte, MG, 31270-901, Brazil.
authors: Miriam Teresa Paz
authors: MT
authors: Lopes
authors: Departamento de Química, ICE, Universidade Federal de Juiz de Fora, Juiz De Fora, MG, 36036-900, Brazil.
authors: Charlane Cimini
authors: CC
authors: Corrêa
authors: Departamento de Química, ICE, Universidade Federal de Juiz de Fora, Juiz De Fora, MG, 36036-900, Brazil.
authors: Hélio F
authors: HF
authors: Dos Santos
authors: Departamento de Química, ICE, Universidade Federal de Juiz de Fora, Juiz De Fora, MG, 36036-900, Brazil.
authors: Mauro Vieira
authors: MV
authors: de Almeida
authors: Departamento de Química, ICE, Universidade Federal de Juiz de Fora, Juiz De Fora, MG, 36036-900, Brazil. hevelinequi@gmail.com.
authors: Heveline
authors: H
authors: Silva
mesh_terms: D000218:Adamantane / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001393:Azoles / Q000737:chemistry*; D045744:Cell Line, Tumor; D006224:Cricetinae; D006046:Gold / Q000737:chemistry*; D006801:Humans; D051379:Mice; D013057:Spectrum Analysis / Q000379:methods; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D001393:Azoles; D006046:Gold; D013880:Thioredoxin-Disulfide Reductase; D000218:Adamantane
keywords: Crystallography; DFT calculations; Molecular docking; Oxadiazol; Phosphine; Thiazolidine; Thioredoxin reductase