Chemistry and Biology of Two Novel Gold(I) Carbene Complexes as Prospective Anticancer Agents

Two
novel gold carbene compounds, namely, chlorido (1-butyl-3-methyl-imidazole-2-ylidene)
gold­(I) (1) and bis­(1-butyl-3-methyl-imidazole-2-ylidene)
gold­(I) (2), were prepared and characterized as prospective
anticancer drug candidates. These compounds consist of a gold­(I) center
linearly coordinated either to one N-heterocyclic carbene (NHC) and
one chloride ligand (1) or to two identical NHC ligands
(2). Crystal structures were solved for both compounds,
the resulting structural data being in good agreement with expectations.
We wondered whether the presence of two tight carbene ligands in 2 might lead to biological properties distinct from those
of the monocarbene complex 1. Notably, in spite of their
appreciable structural differences, these two compounds manifested
similarly potent cytotoxic actions in vitro when challenged against
A2780 human ovarian carcinoma cells. In addition, both were able to
overcome resistance to cisplatin in the A2780R line. Solution studies
revealed that these gold carbene complexes are highly stable in aqueous
buffers at physiological pH. Their reactivity with proteins was explored:
no adduct formation was detected even upon a long incubation with
the model proteins cytochrome c and lysozyme; in contrast, both compounds
were able to metalate, to a large extent, the copper chaperone Atox-1,
bearing a characteristic CXXC motif. The precise nature of the resulting
gold-Atox-1 adducts was elucidated through ESI-MS analysis. On the
basis of these findings, it is proposed that the investigated gold­(I)
carbene compounds are promising antiproliferative agents warranting
a wider pharmacological evaluation. Most likely these gold compounds
produce their potent biological effects through selective metalation
and impairment of a few crucial cellular proteins.