Novel Electrophilic Amides Amenable by the Ugi Reaction Perturb Thioredoxin System via Thioredoxin Reductase 1 (TrxR1) Inhibition: Identification of DVD-445 as a New Lead Compound for Anticancer Therapy
European Journal of Medicinal Chemistry
2019
M. Jovanovic,
D. Zhukovsky,
A. Podolski-Renic,
I. Domračeva,
Raivis Žalubovskis,
M. Sencanski,
S. Glišic,
V. Sharoyko,
T. Tennikova,
D. Dar`in,
M. Pešic,
M. Krasavin
A series of peptidomimetic compounds incorporating an electrophilic moiety was synthesized using the Ugi reaction. These compounds (termed the Ugi Michael acceptors or UMAs) were designed to target the selenocysteine catalytic residue of thioredoxin reductase 1 (TrxR1), a promising cancer target. The compounds were assessed for their potential to inhibit TrxR1 using human neuroblastoma (SH-SY5Y) cell lysate. Based on this initial screening, six compounds were selected for testing against recombinant rat TrxR1 and in the insulin assay to reveal low-micromolar to submicromolar potency of these inhibitors. The same frontrunner compounds were evaluated for their ability to exert antiproliferative activity and induce cell death and this activity was compared to the UMA effects on the levels of reactive oxygen and nitrogen species (RONS). Collectively, the UMA compounds class presented itself as a rich source of leads for TrxR1 inhibitor discovery for anticancer application. Compound 7 (DVD-445) was nominated a lead for further optimization.
DOI
10.1016/j.ejmech.2019.111580
Hipersaite
https://www.sciencedirect.com/science/article/pii/S0223523419307147
Jovanovic, M., Zhukovsky, D., Podolski-Renic, A., Domračeva, I., Žalubovskis, R., Sencanski, M., Glišic, S., Sharoyko, V., Tennikova, T., Dar`in, D., Pešic, M., Krasavin, M. Novel Electrophilic Amides Amenable by the Ugi Reaction Perturb Thioredoxin System via Thioredoxin Reductase 1 (TrxR1) Inhibition: Identification of DVD-445 as a New Lead Compound for Anticancer Therapy. European Journal of Medicinal Chemistry, 2019, Vol. 181, Article number 111580. ISSN 0223-5234. Pieejams: doi:10.1016/j.ejmech.2019.111580
Publikācijas valoda
English (en)