Design, synthesis, and biological evaluation of novel derivatives of dithiodiglycolic acid prepared via oxidative coupling of thiols.
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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.
Keywords:TrxR; Anticancer activity; Disulphide inhibitors; Dithiodiglycolic acid
Source:Journal of Enzyme Inhibition and Medicinal Chemistry, 2019, 34, 1, 665-671
- Identification of predictive molecular markers for cancer progression, response to therapy and disease outcome (RS-41031)
- Russian Foundation for BasicResearch [project grant 18–515-76001
- ERA.Net RUS plus joint programmegrant RUS_ST2017-309 and State Education Development Agencyof Republic of Latvia (“THIOREDIN”)
- COST Action CM1407