Gold(I) Carbene Complexes Causing Thioredoxin 1 and Thioredoxin 2 Oxidation as Potential Anticancer Agents

Abstract

Gold(I) complexes with 1,3-substituted imidazole-2-ylidene and benzimidazole-2-ylidene ligands of the type NHC-Au-L (NHC = N-heterocyclic carbene L = Cl or 2-mercapto-pyrimidine) have been synthesized and structurally characterized. The compounds were evaluated for their antiproliferative properties in human ovarian cancer cells sensitive and resistant to cisplatin (A2780S/R), as well in the nontumorigenic human embryonic kidney cell line (HEK-293T), showing in some cases important cytotoxic effects. Some of the complexes were comparatively tested as thioredoxin reductase (TrxR) and glutathione reductase (GR) inhibitors, directly against the purified proteins or in cell extracts. The compounds showed potent and selective TrxR inhibition properties in particular in cancer cell lines. Remarkably, the most effective TrxR inhibitors induced extensive oxidation of thioredoxins (Trxs), which was more relevant in the cancerous cells than in HEK-293T cells. Additional biochemical assays on glutathione systems and reactive oxygen species formation evidenced important differences with respect to the classical cytotoxic Au(I)-phosphine compound auranofin.

First Crystal Structure for a Gold Carbene–Protein Adduct

“…The anticancer activity of these compounds seems to arise from potent and selective inhibition of the enzyme thioredoxin reductase (TrxR), particularly in cancer cells [27][28][29][30][31][32][33][34][35][36][37][38] , though this mechanistic issue is still highly controversial and debated. Electrospray ionization mass spectrometry (ESI MS) measurements suggest that gold carbene compounds preferentially bind to free cysteine (or seleno-cysteine) side chains [39][40] , with AuNHC + fragments or Au + ions coordinating the thiol (selenol) group upon release of the carbene ligand(s) [39][40] .…”

Facile Suzuki-Miyaura coupling of activated aryl halides using new CpNiBr(NHC) complexes

“…This is mainly due to the support that NHCs provide through the possibility of reliable, predictable, and extensive steric-and electronic tuning [2,3b,5-7] in the design of a model complex with the specific application in mind. With the ever-increasing number of transition metal-NHCs reported, NHC-complexes of Rh [3a,8], Ru [9], Ni [7,[10][11][12][13][14], Pd [4a,6b,15,16], Ag [17], and Au [17,18] remain to be the most abundant in literature, noting that Ni-NHC complexes received considerable attention only during the last decade [11,13,14]. The reaction of nickelocene with bis(alkyl/aryl)imidazolium halides to yield the complexes [CpNiX(NHC)] (X = Cl, Br, I), represents one of the most frequently employed and facile routes into cyclopentadienyl nickel(II) NHC systems [7,[11][12][13]19,[21][22].…”

Current Researches and Applications of Azole-BasedSupermolecules as Medicinal Agents

“…这主 要是由于氯与金的结合不稳定, 使得氯很活泼, 容易被 癌细胞内的活性组分灭活. 在验证选择性的实验中发 现, 抗癌活性高的 11b 对细胞质硫氧还蛋白还原酶 TrxR1 活性的抑制很强, IC 50 值为 4.9 nmol/L, 但是对线 粒体基质硫氧还蛋白还原酶 TrxR2 抑制能力减弱, IC 50 值大于 100 nmol/L, 这说明金(I)氮杂环卡宾 11b 的作用 靶点可能是癌细胞细胞质硫氧还蛋白还原酶 TrxR1 [73] .…”