Thioamido coordination in a thioxo-1,2,4-triazole copper(II) complex enhances nonapoptotic programmed cell death associated with copper accumulation and oxidative stress in human cancer cells.
The thioamido function of [CuCl2(1H)]Cl (2) (1=4-amino-1,4-dihydro-3-(2-pyridyl)-5-thioxo-1,2,4-triazole), a cytotoxic copper complex, was converted into thioether moieties, leading to the synthesis of [CuCl2(3)]2 (4) and [CuCl2(5)] (6) (3=6-methyl-3-pyridin-2-yl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine; 5=4-amino-5-ethylthio-3-(2-pyridyl)-1,2,4-triazole). These complexes were structurally characterized, and their stability constants, along with their biological activity, were determined. 4 and 6 were slightly less stable and significantly less active than 2. However, as 2, both complexes induced nonapoptotic vacuolar cell death. Copper uptake, investigated in both 2-sensitive and -insensitive cell types, was markedly higher in sensitive cells where it was associated with an increase in oxidized glutathione. These data suggest that the thioamido function enhances the cytotoxicity of copper complexes in cancer cells promoting the accumulation of the metal and its interaction with cell thiols.
Tardito
Saverio
S
Dipartimento di Chimica Generale ed Inorganica, Chimica Analitica, Chimica Fisica, Università degli Studi di Parma, Viale G.P. Usberti 17/A, 43100 Parma, Italy.
Bussolati
Ovidio
O
Maffini
Monica
M
Tegoni
Matteo
M
Giannetto
Marco
M
Dall'asta
Valeria
V
Franchi-Gazzola
Renata
R
Lanfranchi
Maurizio
M
Pellinghelli
Maria Angela
MA
Mucchino
Claudio
C
Mori
Giovanni
G
Marchio
Luciano
L
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000737:chemistry*; D003300:Copper; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000970:Antineoplastic Agents; D002614:Chelating Agents; D009942:Organometallic Compounds; D017382:Reactive Oxygen Species; D014230:Triazoles; D003300:Copper