Research output: Contribution to journal › Article › peer-review
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. / 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.
In: European Journal of Medicinal Chemistry, Vol. 181, 111580, 01.11.2019.Research output: Contribution to journal › Article › peer-review
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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 -
ID: 47798794