Further exploration of DVD-445 as a lead thioredoxin reductase (TrxR) inhibitor for cancer therapy: Optimization of potency and evaluation of anticancer potential

  • Eur J Med Chem. 2020 Apr 1:191:112119. doi: 10.1016/j.ejmech.2020.112119.
Mirna Jovanović  1 ,  Daniil Zhukovsky  2 ,  Ana Podolski-Renić  1 ,  Raivis Žalubovskis  3 ,  Dmitry Dar'in  2 ,  Vladimir Sharoyko  2 ,  Tatiana Tennikova  2 ,  Milica Pešić  4 ,  Mikhail Krasavin  5
Affiliations
  • 1. Institute for Biological Research "Siniša Stanković" - National Institute of Republic of Serbia, University of Belgrade, 11060, Belgrade, Serbia.
  • 2. Saint Petersburg State University, Saint Petersburg, 199034, Russian Federation.
  • 3. Latvian Institute of Organic Synthesis, Riga, LV-1006, Latvia; Institute of Technology of Organic Chemistry, Faculty of Materials Science and Applied Chemistry, Riga Technical University, Riga, LV-1048, Latvia.
  • 4. Institute for Biological Research "Siniša Stanković" - National Institute of Republic of Serbia, University of Belgrade, 11060, Belgrade, Serbia. Electronic address: [email protected].
  • 5. Saint Petersburg State University, Saint Petersburg, 199034, Russian Federation. Electronic address: [email protected].
PMID: 32087464 DOI: 10.1016/j.ejmech.2020.112119
Abstract

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.