N
-Heterocyclic carbene (NHC) gold(I) complexes offer great
prospects in medicinal chemistry as antiproliferative, anticancer,
and antibacterial agents. However, further development requires a
thorough understanding of their reaction behavior in aqueous media.
Herein, we report the conversion of the bromido[3-ethyl-4-(4-methoxyphenyl)-5-(2-methoxypyridin-5-yl)-1-propylimidazol-2-ylidene]gold(I)
((NHC)Au
I
Br,
1
) complex in acetonitrile/water
mixtures to the bis[3-ethyl-4-(4-methoxyphenyl)-5-(2-methoxypyridin-5-yl)-1-propylimidazol-2-ylidene]gold(I)
([(NHC)
2
Au
I
]
+
,
7
), which
is subsequently oxidized to the dibromidobis[3-ethyl-4-(4-methoxyphenyl)-5-(2-methoxypyridin-5-yl)-1-propylimidazol-2-ylidene]gold(III)
([(NHC)
2
Au
III
Br
2
]
+
,
9
). By combining experimental data from HPLC, NMR, and (LC-)/HR-MS
with computational results from DFT calculations, we outline a detailed
ligand scrambling reaction mechanism. The key step is the formation
of the stacked ((NHC)Au
I
Br)
2
dimer (
2
) that rearranges to the T-shaped intermediate Br(NHC)
2
Au
I
–Au
I
Br (
3
). The dissociation
of Br
–
from
3
and recombination lead
to (NHC)
2
Au
I
–Au
I
Br
2
(
5
) followed by the separation into [(NHC)
2
Au
I
]
+
(
7
) and [Au
I
Br
2
]
−
(
8
). [Au
I
Br
2
]
−
is not stable in an aqueous environment
and degrades in an internal redox reaction to Au
0
and Br
2
. The latter in turn oxidizes
7
to the gold(III)
species
9
. The reported ligand rearrangement of the (NHC)Au
I
Br complex differs from that found for related silver(I) analogous.
A detailed understanding of this scrambling mechanism is of utmost
importance for the interpretation of their biological activity and
will help to further optimize them for biomedical and other applications.
Bromido[3-ethyl-4-aryl-5-(2-methoxypyridin-5-yl)-1-propyl-1,3-dihydro-2H-imidazol-2-ylidene]gold(i) complexes (8a–h) with methoxy, methyl and fluorine substituents at different positions in the 4-aryl ring were synthesized and characterized.
The significance of the halido ligand (Cl-, Br-, I-) in halido[3-ethyl-4-phenyl-5-(2-methoxypyridin-5-yl)-1-propyl-1,3-dihydro-2H-imidazol-2-ylidene]gold(I) complexes (2, 3, 4) in terms of ligand exchange reactions, including the ligand scrambling to the bis[3-ethyl-4-phenyl-5-(2-methoxypyridin-5-yl)-1-propyl-1,3-dihydro-2H-imidazol-2-ylidene]gold(I) complex (5)...
The known ruthenium complex [Ru(tpy)(bpy)(Hmte)](PF6)2 ([1](PF6)2, where tpy = 2,2’:6’,2″-terpyridine, bpy = 2,2’-bipyridine, Hmte = 2-(methylthio)ethanol) is photosubstitutionally active but non-toxic to cancer cells even upon light irradiation. In this work, the two analogs complexes [Ru(tpy)(NN)(Hmte)](PF6)2, where NN = 3,3'-biisoquinoline (i-biq, [2](PF6)2) and di(isoquinolin-3-yl)amine (i-Hdiqa, [3](PF6)2), were synthesized and their photochemistry and phototoxicity evaluated to assess their suitability as photoactivated chemotherapy (PACT) agents. The increase of the aromatic surface of [2](PF6)2 and [3](PF6)2, compared to [1](PF6)2, leads to higher lipophilicity and higher cellular uptake for the former complexes. Such improved uptake is directly correlated to the cytotoxicity of these compounds in the dark: while [2](PF6)2 and [3](PF6)2 showed low EC50 values in human cancer cells, [1](PF6)2 is not cytotoxic due to poor cellular uptake. While stable in the dark, all complexes substituted the protecting thioether ligand upon light irradiation (520 nm), with the highest photosubstitution quantum yield found for [3](PF6)2 (Φ[3] = 0.070). Compounds [2](PF6)2 and [3](PF6)2 were found both more cytotoxic after light activation than in the dark, with a photo index of 4. Considering the very low singlet oxygen quantum yields of these compounds, and the lack of cytotoxicity of the photoreleased Hmte thioether ligand, it can be concluded that the toxicity observed after light activation is due to the photoreleased aqua complexes [Ru(tpy)(NN)(OH2)]2+, and thus that [2](PF6)2 and [3](PF6)2 are promising PACT candidates.
Graphic abstract
A series of bis[3-ethyl-4-aryl-5-(2-methoxypyridin-5-yl)-1-propyl-1,3-dihydro-2H-imidazol-2-ylidene]gold(I) complexes (2a-f) containing methyl, fluoro or methoxy substituents at various positions in the 4-aryl ring were synthe-sized and evaluated for their anti-cancer properties in A2780 (wild-type...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.