Design, synthesis, and biological evaluation of novel derivatives of dithiodiglycolic acid prepared via oxidative coupling of thiols

Abstract

Human thioredoxin reductase 1 (TrxR1) is a selenocysteine-containing enzyme which plays a crucial role in regulating numerous redox signalling pathways within the cell. While its functioning is important in all cells, levels of TrxR1 expression are higher in cancer cells, possibly as an adaptation to much higher levels of reactive oxygen species and the need for more extensive DNA synthesis. This makes TrxR1 an attractive target for cancer therapy development. Inspired by the structure of disulphide compounds which have advanced through various stages of clinical development, we designed a series of dithiodiglycolic acid derivatives. These were prepared from respective thiol synthons using an iodine- or benzotriazolyl chloride-promoted oxidative disulphide bond formation. Inhibition of TrxR present in cell lysates from human neuroblastoma cells (SH-SY5Y) and rat liver cells indicated several compounds with a potential for TrxR inhibition. Some of these compounds were also tested for growth inhibition against two human cancer cell lines and normal human keratinocytes.

Ru(III) Complexes with Lonidamine-Modified Ligands

“…Complexes 16 and 20 inhibited the activity of isolated rat TrxR1 at micromolar concentrations: IC 50 (16) = 20.4 ± 0.1 µM and IC 50 (20) = 8.5 ± 0.3 µM. We demonstrated the efficacy of 16 and 20 as modulators of intracellular TrxR1 using rat liver extracts and varying concentrations of each complex (Figure 7 and Table S1; see Experimental for details) [47].…”

Licochalcone E inhibits trxR1 expression, alters Nrf2/STAT6 signal, and induces antitumor effects in vitro against human SH‐SY5Y and SK‐N‐BE(2) neuroblastoma cells

“…Moreover, previously reports suggested that TrxR1 was high expressed in many cancer cells and acted as a promising target for cancer therapy 26 . Also, important evidence showed that TrxR1 inhibitors valuable for growth inhibition against human cancer cell line SH‐SY5Y, and may be act as an attractive target for cancer therapy 27 . A recent evidence demonstrated that Licochalcone A administration suppressed cell apoptosis through reducing the expression of TrxR1 in colorectal cancer cells 28 .…”

“…26 Also, important evidence showed that TrxR1 inhibitors valuable for growth inhibition against human cancer cell line SH-SY5Y, and may be act as an attractive target for cancer therapy. 27 A recent evidence demonstrated that Licochalcone A administration suppressed cell apoptosis through reducing the expression of TrxR1 in colorectal cancer cells. 28 In agreement with this article, the present study confirmed that LicE treatment significant inhibited TrxR1 expression in NB cell lines SH-SY5Y and SK-N-BE(2) at mRNA and protein levels.…”

Sulfocoumarins as dual inhibitors of human carbonic anhydrase isoforms IX/XII and of human thioredoxin reductase

“…Another principal mechanism of tumour survival which we have been recently tackling 11,12 as a target for anticancer agent design, is that providing tumour cell defence against oxidative stress (reactive oxygen species or ROS). In particular, tumour cells have been shown to overexpress thioredoxin reductase (TrxR, EC 1.8.1.9) which contributes to their resistant phenotype characterised by higher levels of ROS 13 .…”