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

Mirna Jovanović; Daniil Zhukovsky; Ana Podolski-Renić; Raivis Žalubovskis; Dmitry Dar'in; Vladimir Sharoyko; Tatiana Tennikova; Milica Pešić; Mikhail Krasavin

doi:10.1016/j.ejmech.2020.112119

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. Epub 2020 Feb 6.

Authors

Mirna Jovanović¹, Daniil Zhukovsky², Ana Podolski-Renić¹, Raivis Žalubovskis³, Dmitry Dar'in², Vladimir Sharoyko², Tatiana Tennikova², Milica Pešić⁴, Mikhail Krasavin⁵

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: camala@ibiss.bg.ac.rs.
⁵ Saint Petersburg State University, Saint Petersburg, 199034, Russian Federation. Electronic address: m.krasavin@spbu.ru.

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.

MeSH terms

ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Proliferation / drug effects
Cell Survival / drug effects
Cells, Cultured
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Humans
Molecular Structure
Oxidative Stress / drug effects
Recombinant Proteins / metabolism
Structure-Activity Relationship
Thioredoxin Reductase 1 / antagonists & inhibitors*
Thioredoxin Reductase 1 / metabolism

Substances

ATP Binding Cassette Transporter, Subfamily B, Member 1
Antineoplastic Agents
Enzyme Inhibitors
Recombinant Proteins
TXNRD1 protein, human
Thioredoxin Reductase 1