Triethylphosphinegold(I) Complexes with Secnidazole-Derived Thiosemicarbazones: Cytotoxic Activity against HCT-116 Colorectal Cancer Cells under Hypoxia Conditions

Triethylphosphinegold­(I)
complexes [Au­(HL1)­P­(CH2CH3)3]­PF6 (1), [Au­(HL2)­P­(CH2CH3)3]­PF6 (2), and [Au­(HL3)­P­(CH2CH3)3]­PF6 (3) were
obtained with (E)-2-(1-(2-methyl-5-nitro-1H-imidazol-1-yl)­propan-2-ylidene)­hydrazinecarbothioamide
(HL1), (E)-N-methyl-2-(1-(2-methyl-5-nitro-1H-imidazol-1-yl)­propan-2-ylidene)­hydrazinecarbothioamide
(HL2), and (E)-2-(1-(2-methyl-5-nitro-1H-imidazol-1-yl)­propan-2-ylidene)-N-phenylhydrazinecarbothioamide (HL3). All
compounds were assayed for their cytotoxic activities against HCT-116
colorectal carcinoma cells under normoxia and hypoxia conditions and
against nonmalignant HEK-293 human embryonic kidney cells under normoxia
conditions. The thiosemicarbazone ligands HL1-HL3 were inactive against HCT-116 cells under hypoxia but while HL3 was inactive, HL1 and HL2 proved
to be cytotoxic to both cell lineages under normoxia conditions. Complexes
(1–3) and the triethylphosphinegod­(I)
precursor proved to be active against both cell lineages in normoxia
as well as in hypoxia. While 1 and 3 revealed
to be active against HEK-293 and HCT-116 cells, being approximately
as active against HCT-116 cells in normoxia as under hypoxia, complex
(2) proved to be more active against HCT-116 cells under
hypoxia than under normoxia conditions, and more active against HCT-116
cells than against the nonmalignant HEK-293 cells, with the selectivity
index, calculated as SI = IC50HEK‑293/IC50HCT‑116hypoxia, equal to 3.7, similar to the value obtained for the control drug
tirapazamine (tirapazamine (TPZ), SI = 4). Although the compounds
showed distinct cytotoxic activities, the electrochemical behaviors
of HL1-HL3 were very similar, as were the
behaviors of complexes (1–3). Complex
(2) deserves special interest since it was significantly
more active under hypoxia than under normoxia conditions. Hence, in
this case, selective reduction of the nitro group in a low oxygen
pressure environment, resulting in toxic reactive oxygen species (ROS)
and damage to DNA or other biomolecules, might operate, while for
the remaining compounds, other modes of action probably occur.