Further Exploration of DVD-445 as a Lead Thioredoxin Reductase (TrxR) Inhibitor for Cancer Therapy: Optimization of Potency and Evaluation of Anticancer Potential

European Journal of Medicinal Chemistry 2020
Mirna Jovanovic, Daniil Zhukovsky, Ana Podolski-Renic, Raivis Žalubovskis, Dmitry Dar`in, Vladimir Sharoyko, Tatiana Tennikova, Milica Pešic, Mikhail Krasavin

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.

Keywords
Cancer cell defense mechanism, Covalent inhibitor, Michael acceptors, Oxidative stress, P-gp inhibition, Thioredoxin reductase, Ugi four-component reaction
DOI
10.1016/j.ejmech.2020.112119
Hyperlink
https://www-sciencedirect-com.resursi.rtu.lv/science/article/pii/S0223523420300866?via%3Dihub

Jovanovic, M., Zhukovsky, D., Podolski-Renic, A., Žalubovskis, R., Dar`in, D., Sharoyko, V., Tennikova, T., Pešic, M., Krasavin, M. Further Exploration of DVD-445 as a Lead Thioredoxin Reductase (TrxR) Inhibitor for Cancer Therapy: Optimization of Potency and Evaluation of Anticancer Potential. European Journal of Medicinal Chemistry, 2020, Vol. 191, Article number 112119. ISSN 0223-5234. e-ISSN 1768-3254. Available from: doi:10.1016/j.ejmech.2020.112119

Publication language
English (en)