TY - JOUR

T1 - Novel electrophilic amides amenable by the Ugi reaction perturb thioredoxin system via thioredoxin reductase 1 (TrxR1) inhibition

T2 - Identification of DVD-445 as a new lead compound for anticancer therapy

AU - Jovanović, Mirna

AU - Zhukovsky, Daniil

AU - Podolski-Renić, Ana

AU - Domračeva, Ilona

AU - Žalubovskis, Raivis

AU - Senćanski, Milan

AU - Glišić, Sanja

AU - Sharoyko, Vladimir

AU - Tennikova, Tatiana

AU - Dar'in, Dmitry

AU - Pešić, Milica

AU - Krasavin, Mikhail

PY - 2019/11/1

Y1 - 2019/11/1

N2 - 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.

AB - 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.

KW - Amides/chemistry

KW - Antineoplastic Agents/chemistry

KW - Catalytic Domain/drug effects

KW - Cell Line, Tumor

KW - Cell Proliferation/drug effects

KW - Humans

KW - Molecular Docking Simulation

KW - Neoplasms/drug therapy

KW - Thioredoxin Reductase 1/antagonists & inhibitors

KW - Thioredoxins/metabolism

KW - SELENOCYSTEINE

KW - CANCER

KW - GLIOBLASTOMA

KW - SELENOPROTEINS

KW - CELL-CYCLE

KW - STRESS

KW - EXPRESSION

UR - http://www.scopus.com/inward/record.url?scp=85073183701&partnerID=8YFLogxK

U2 - 10.1016/j.ejmech.2019.111580

DO - 10.1016/j.ejmech.2019.111580

M3 - Article

C2 - 31400708

AN - SCOPUS:85073183701

VL - 181

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

SN - 0223-5234

M1 - 111580

ER -