Further exploration of DVD-445 as a lead thioredoxin reductase (TrxR) inhibitor for cancer therapy: Optimization of potency and evaluation of anticancer potential.
Article (Published version)
© 2020 Elsevier Masson SAS.
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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
Source:European Journal of Medicinal Chemistry, 2020, 191, 112119-
- Identification of predictive molecular markers for cancer progression, response to therapy and disease outcome (RS-41031)
- ERA.Net RUS plus joint program grant RUS_ST2017-309
- Russian Foundation for Basic Research (project grant 18–515-76001)
- State Education Development Agency of Republic of Latvia (“THIOREDIN”)