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

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. Th...

Full description

Saved in:
Bibliographic Details
Published inEuropean journal of medicinal chemistry Vol. 181; p. 111580
Main Authors Jovanović, Mirna, Zhukovsky, Daniil, Podolski-Renić, Ana, Domračeva, Ilona, Žalubovskis, Raivis, Senćanski, Milan, Glišić, Sanja, Sharoyko, Vladimir, Tennikova, Tatiana, Dar'in, Dmitry, Pešić, Milica, Krasavin, Mikhail
Format Journal Article
LanguageEnglish
Published ISSY-LES-MOULINEAUX Elsevier Masson SAS 01.11.2019
Elsevier
Subjects
Online AccessGet full text

Cover

Loading…
More Information
Summary: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. [Display omitted] •New electrophilic inhibitors of thioredoxin reductase 1 are described.•Compounds are accessed via the Ugi reaction and target the catalytic selenocysteine.•6 compounds were shown to inhibit TrxR1 in three different assays.•This activity was corroborated by covalent docking simulation.•The enzyme inhibition translated into cellular activity.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2019.111580