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A Sugar‐Modified Phosphole Gold Complex with Antiproliferative Properties Acting as a Thioredoxin Reductase Inhibitor in MCF‐7 Cells

TrxR possesses a Cys SeCys catalytic pair in the more flexible C-terminal domain, in addition to the N-terminal Cys XXXX Cys active site. Trx contains a Cys pair which, in a reduced state, is essential for reducing disulfide bridges critical for protein activity. TrxR and Trx form an important redox system involved in multiple physiological processes. Reduced thioredoxin can provide reducing equivalents to a number of proteins including ribonucleotide reductase, which is involved in DNA synthesis and consequently in cell proliferation. The TrxR/Trx system is also involved in the cellular protection from or repair following oxidative stress, and in the regeneration of antioxidants such as vitamin C, ubiquinone, and lipoic acid. Additionally, the TrxR/Trx system modulates the activity of transcription factors involved in various signaling pathways related to apoptosis and cellular response to growth factors. TrxR and Trx have been shown to be overexpressed in several tumor types, and increased levels are known to regulate both cancer cell growth and survival. Furthermore, overexpression appears to be correlated with chemotherapeutic resistance, aggressive tumor types and poor prognosis. Taken together, these observations present the TrxR/Trx system as a target of interest for the development of new anticancer agents. Several TrxR inhibitors have already been identified and have shown growth inhibition against tumor cells (for a recent review, see ref. [6]). Among those, metal–ligand complexes are of particular interest because of their combined abilities to irreversibly target the dithiol/selenol catalytic pair essential for TrxR activity and bind DNA. Nine compounds have been evaluated in the present study for their cytotoxic activities against the human breast cancer MCF-7 cell line using a flow cytometric analysis with 2’, 7’-dichlorodihydrofluorescein diacetate (H2DCFDA) and propidium iodide (PI) staining. These compounds were selected or designed with the aim of targeting disulfide reductase activity known to be overexpressed in cancer. Analogues 1 and 2 (Figure 1) are metal-free phosphole ligands and derivative 3 has shown slight cytotoxicity in B16 melanoma and P388 leukemia cells. Phosphine-coordinated gold(I) thiosugar complexes such as auranofin (4) was developed for the treatment of rheumatoid arthritis, a disorder associated with TrxR overexpression, and reported to inhibit the purified TrxR from human placenta. Phosphole-containing gold and platinum complexes 5, 6, 7 and GoPI (8, {1-phenyl-2,5-di(2-pyridyl)phosphole}AuCl) are irreversible inhibitors of purified human GR and TrxR. 15]