TrxR inhibition and antiproliferative activities of structurally diverse gold N-heterocyclic carbene complexes

Abstract

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.

Exploring the potential of gold(iii) cyclometallated compounds as cytotoxic agents: variations on the C^N theme

“…[8][9][10][11][12] The advantage of NHC and cyclometallated organometallic gold compounds is their relative stability with respect to other classical coordination complexes. There is evidence that Au compounds preferentially target proteins in biological environments, such as the Se-enzyme thioredoxin reductase (TrxR), [13][14][15][16] Zn finger enzymes, 17,18 as well as the membrane water and glycerol channel aquaglyceroporins. [19][20][21] Notably, increasing interest is focused on the family of cyclometallated gold(III) complexes, in which the Au 3+ ions are highly stabilized under physiological conditions.…”

Gold(i) thiotetrazolates as thioredoxin reductase inhibitors and antiproliferative agents

“…Notably, strong TrxR inhibition with thiophenolate containing gold(I) carbene complexes was also observed in a previous study. 34 However, the enhanced activity against TrxR did not translate into elevated cytotoxicity since complexes 2a-e were of comparable activity with 1a and 1b in cell proliferation assays.…”

Pyrimidine Derivatives with Terminal Pyridyl Heterocycles: Facile Synthesis and Their Antiproliferative Activities

“…HT‐29 colon carcinoma cells, MDA‐MB‐231 breast cancer cells, MCF‐7 breast carcinoma cells were maintained in Dulbecco's Modified Eagle Medium (4.5 g/L (D)‐glucose, L ‐glutamine, pyruvate), which was supplemented with gentamycin (50 mg/L)and fetal bovine serum superior, standardized (Biochrom GmbH, Berlin) (10% v/v), and were passaged once a week. Determination of antiproliferative effects involved the following protocol described by Ott and coworkers . One hundred microliters of cells (HT‐29: 2565 cells/mL, MCF‐7: 4840 cells/mL, MDA‐MB‐231: 4120 cells/mL, or RC‐124: 1460 cells/mL) were seeded into the wells of 96‐well plates and incubated at 37°C/5% CO 2 atmosphere) for 48 h (HT‐29) or 72 h (MCF‐7, MDA‐MB‐231, and RC‐124).…”