Gold compounds with N-heterocyclic carbene (NHC) ligands have been widely described as potent thioredoxin reductase (TrxR) inhibitors and effective anticancer agents. However, despite these promising aspects structure-activity-relationship (SAR) studies still remain limited. In this study a structurally diverse library of gold(I) and gold(III) NHC complexes was investigated for inhibitory capacity against TrxR and for antiproliferative activity in HT-29 human colon adenocarcinoma cells with the aim of identifying a valid SAR. Overall results indicated that the bioactivity, carried by the gold center, is intimately linked to the chemical properties of the residues at the NHC scaffold as well as other ligands coordinated to the gold atom. Although a direct correlation between IC 50 values for cytotoxicity and enzyme inhibition could not be established, the inhibition of TrxR represents an important parameter to achieve a good cytotoxic activity.
The pyridazine-bridged NHC/pyrazole ligand L (HL = 3-[3-(2,4,6-trimethylphenyl)-3H-imidazolium-1-yl]-6-(3,5-dimethylpyrazol-1-yl)-pyridazine)
that provides an organometallic and a classical N-donor compartment
is shown to serve as a versatile scaffold for a variety of homo- and
heterometallic gold(I) carbene complexes. Complexes [LAuX] (1
Cl
, X = Cl; 1
Br
, X = Br), [L2Au](PF6) (2), [L2AuAg](BF4)(PF6) (3), [L2AuAg3(MeCN)6](BF4)4 (5), and [L2AuCu](OTf)0.75(PF6)1.25 (6) have been
characterized by X-ray crystallography. In all cases Au(I) binds to
the NHC site while the additional Ag(I) in 3 or Cu(I)
in 6 is accommodated in the pyrazole-derived site. Both 3 and 6 form two-stranded helical structures;
racemization of the P and M enantiomers
is much more facile in the Ag(I) case 3 but has a barrier
of around 65 kJ/mol in the Cu(I) case 6, which is rationalized
on the basis of the different coordination chemistry preferences of
these two metal ions. 3 may bind two further Ag(I) ions
to the central pyridazine N, giving 5. Treatment of 1
Br
with Br2 leads to bromination
at the pyrazole C4 of the ligand backbone, yielding [LBrAuBr] (8). In contrast, 1
Cl
could be successfully oxidized to the Au(III) complex
[LAuCl3] (7) using PhICl2; both 7 and the gold(I) complex 8 have been characterized
crystallographically. Preliminary screening shows that 7, in combination with AgBF4, is a good catalyst for the
etherification of 1-indanol with a variety of alcohol substrates and
shows significantly higher activity than the gold(I) catalyst 1
Cl
.
A family of new pyridazine‐bridged NHC/pyrazole ligand precursors HL1–5 were prepared and fully characterized including analysis by XRD {HL1 = 3‐[3‐(2,6‐diisopropylphenyl)‐3H‐imidazolium‐1‐yl]‐6‐(3‐pyridin‐2‐yl‐pyrazol‐1‐yl)‐pyridazine, HL2 = 3‐[3‐(2,4,6‐trimethylphenyl)‐3H‐imidazolium‐1‐yl]‐6‐(3‐pyridin‐2‐yl‐pyrazol‐1‐yl)‐pyridazine, HL3 = 3‐[3‐(2,4,6‐trimethylphenyl)‐3H‐imidazolium‐1‐yl]‐6‐(3,5‐dimethylpyrazol‐1‐yl)‐pyridazine, HL4 = 3‐(3‐tert‐butyl‐3H‐imidazolium‐1‐yl)‐6‐(3,5‐dimethylpyrazol‐1‐yl)‐pyridazine, HL5 = 3‐[3‐(2,4,6‐trimethylphenyl)‐3H‐imidazolium‐1‐yl]‐6‐(3‐methyl‐5‐phenylpyrazol‐1‐yl)‐pyridazine, X = PF6– or BF4–}. Reaction of the ligand precursors with Ag2O yielded various silver(I) complexes whose structures have been elucidated crystallographically. In complexes [(L3)2Ag](PF6) (4) and[(L4)2Ag](PF6) (4′) the single silver(I) ion is coordinated in a linear fashion by the NHC moieties of the two ligand strands. An NMR titration with AgBF4 reveals that 4 can bind two more silver(I) ions. The complex [(L5)2Ag2](PF6)2 (5′) features an additional silver(I) centre bound to the two pyrazole rings, whereas in [(L3)2Ag2](BF4)2 (6) ligand reshuffling has occurred to give antiparallel ligand strands with {CNHCNpyrazole} coordination of each metal ion. Secondary interactions with the pyridazine N‐atom are observed in some cases. An additional third silver(I) ion can be accommodated between the central pyridazine bridges, as shown in [(L3)2Ag3](PF6)2(BF4) (7). The sequence of binding events and the identity of the species in solution have been investigated by NMR spectroscopy and ESI mass spectrometry.
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