Thioredoxin Reductase and Organometallic Complexes: A Pivotal System to Tackle Multidrug Resistant Tumors?

Cancers classified as multidrug-resistant (MDR) are a family of diseases with poor prognosis despite access to increasingly sophisticated treatments. Several mechanisms explain these resistances involving both tumor cells and their microenvironment. It is now recognized that a multi-targeting approach offers a promising strategy to treat these MDR tumors. Inhibition of thioredoxin reductase (TrxR), a key enzyme in maintaining redox balance in cells, is a well-identified target for this approach. Auranofin was the first inorganic gold complex to be described as a powerful inhibitor of TrxR. In this review, we will first recall the main results obtained with this metallodrug. Then, we will focus on organometallic complexes reported as TrxR inhibitors. These include gold(I), gold(III) complexes and metallocifens, i.e., organometallic complexes of Fe and Os derived from tamoxifen. In these families of complexes, similarities and differences in the molecular mechanisms of TrxR inhibition will be highlighted. Finally, the possible relationship between TrxR inhibition and cytotoxicity will be discussed and put into perspective with their mode of action.

α-Hydroxylactams as Efficient Entries to Diversely Functionalized Ferrociphenols: Synthesis and Antiproliferative Activity Studies.

The [ferrocene-ene-phenol] motif has been identified as the pharmacophore responsible for the anticancer activity of the family of ferrocene-based molecules coined ferrocifens, owing to its unique redox properties. The addition of imide entities to the historical ferrociphenol scaffold tremendously enhanced the cytotoxic activity of a large panel of cancer cell cultures and preliminary studies showed that the reduction of one of the carbonyl groups of the imide groups to the corresponding α-hydroxylactams only slightly affected the antiproliferative activity. As a continuation to these studies, we took advantage of the facile conversion of α-hydroxylactams to highly electrophilic N-acyliminium ions to graft various substituents to the imide motif of phthalimido ferrocidiphenol. Cell viability studies showed that the newly synthesized compounds showed diverse cytotoxic activities on two breast cancer cell lines, while only one compound was significantly less active on the non-tumorigenic cell line hTERT-RPE1.

Identification of Three-Way DNA Junction Ligands through Screening of Chemical Libraries and Validation by Complementary in Vitro Assays.

The human genome is replete with repetitive DNA sequences that can fold into thermodynamically stable secondary structures such as hairpins and quadruplexes. Cellular enzymes exist to cope with these structures whose stable accumulation would result in DNA damage through interference with DNA transactions such as transcription and replication. Therefore, the chemical stabilization of secondary DNA structures offers an attractive way to foster DNA transaction-associated damages to trigger cell death in proliferating cancer cells. While much emphasis has been recently given to DNA quadruplexes, we focused here on three-way DNA junctions (TWJ) and report on a strategy to identify TWJ-targeting agents through a combination of in vitro techniques (TWJ-screen, polyacrylamide gel electrophoresis, fluorescence resonance energy transfer-melting, electrospray ionization mass spectrometry, dialysis equilibrium, and sulforhodamine B assays). We designed a complete workflow and screened 1200 compounds to identify promising TWJ ligands selected on stringent criteria in terms of TWJ-folding ability, affinity, and selectivity.