TY - JOUR

T1 - Further exploration of DVD-445 as a lead thioredoxin reductase (TrxR) inhibitor for cancer therapy

T2 - Optimization of potency and evaluation of anticancer potential

AU - Jovanović, Mirna

AU - Zhukovsky, Daniil

AU - Podolski-Renić, Ana

AU - Žalubovskis, Raivis

AU - Dar'in, Dmitry

AU - Sharoyko, Vladimir

AU - Tennikova, Tatiana

AU - Pešić, Milica

AU - Krasavin, Mikhail

PY - 2020/4/1

Y1 - 2020/4/1

N2 - A series of analogs of the earlier reported lead compound DVD-445 (thioredoxin reductase inhibitor with anticancer activity) has been synthesized via a modified Ugi reaction and investigated. Seven most potent compounds (with IC50 below 5.00 μM against recombinant rTrxR1 enzyme) were examined for their effect on cell growth and viability, oxidative stress induction and P-glycoprotein (P-gp) inhibition in human glioblastoma cells cell line U87 and its corresponding multidrug resistant (MDR) cell line U87-TxR. Several of these frontrunner compounds were shown to be superior over DVD-445. Besides providing promising candidates for anticancer therapy, our study further validates the small electrophilic Ugi Michael acceptor (UMA) chemotype as efficacious inhibitor of thioredoxin reductase.

AB - A series of analogs of the earlier reported lead compound DVD-445 (thioredoxin reductase inhibitor with anticancer activity) has been synthesized via a modified Ugi reaction and investigated. Seven most potent compounds (with IC50 below 5.00 μM against recombinant rTrxR1 enzyme) were examined for their effect on cell growth and viability, oxidative stress induction and P-glycoprotein (P-gp) inhibition in human glioblastoma cells cell line U87 and its corresponding multidrug resistant (MDR) cell line U87-TxR. Several of these frontrunner compounds were shown to be superior over DVD-445. Besides providing promising candidates for anticancer therapy, our study further validates the small electrophilic Ugi Michael acceptor (UMA) chemotype as efficacious inhibitor of thioredoxin reductase.

KW - Cancer cell defense mechanism

KW - Covalent inhibitor

KW - Michael acceptors

KW - Oxidative stress

KW - P-gp inhibition

KW - Thioredoxin reductase

KW - Ugi four-component reaction

KW - SMALL-MOLECULE INHIBITORS

KW - CELL-CYCLE

KW - MECHANISMS

KW - DRUG-RESISTANCE

UR - http://www.scopus.com/inward/record.url?scp=85079530936&partnerID=8YFLogxK

U2 - 10.1016/j.ejmech.2020.112119

DO - 10.1016/j.ejmech.2020.112119

M3 - Article

AN - SCOPUS:85079530936

VL - 191

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

SN - 0223-5234

M1 - 112119

ER -