May 1,2-Dithiolane-4-carboxylic Acid and Its Derivatives Serve as a Specific Thioredoxin Reductase 1 Inhibitor?

Abstract

Thioredoxin reductase is an essential enzyme that plays a crucial role in maintaining cellular redox homeostasis by catalyzing the reduction of thioredoxin, which is involved in several vital cellular processes. The overexpression of TrxR is often associated with cancer development. A series of 1,2-dithiolane-4-carboxylic acid analogs were obtained to verify the selectivity of 1,2-dithiolane moiety toward TrxR. Asparagusic acid analogs and their bioisoters remain inactive toward TrxR, which proves the inability of the 1,2-dithiolane moiety to serve as a pharmacophore during the interaction with TrxR. It was found that the Michael acceptor functionality-containing analogs exhibit higher inhibitory effects against TrxR compared to other compounds of the series. The most potent representatives exhibited micromolar TrxR1 inhibition activity (IC₅₀ varied from 5.3 to 186.0 μM) and were further examined with in vitro cell-based assays to assess the cytotoxic effects on various cancer cell lines and cell death mechanisms.

Keywords: 1,2-dithiolane; Michael acceptor; TrxR; asaparagusic acid.

Figure 1

Representation of plausible reaction of TrxR1 selenocysteine residue (in its selenoate form) with Michael acceptor moiety (coumarin).

Scheme 1

Synthetic conditions for the synthesis of analogs 2a–2l.

Figure 2

Representative plots from flow cytometry analysis of cell death after treatment with compound 2k, up to 500 nM final concentrations for 20 h in 4T1 cells (A). Effects of compound 2k on induction of apoptosis, presented as percentage of single cell population (marked with a black contour line in panel (A)) (B) The data are presented as the mean ± SEM of three independent experiments performed in duplicate.