ArticleAntioxidants & redox signaling2013
Identification of Michael acceptor-centric pharmacophores with substituents that yield strong thioredoxin reductase inhibitory character correlated to antiproliferative activity.
Article in Antioxidants & redox signaling, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 94 citations in OpenAlex.
- Furagin Derivatives-Nitrofuran-Based Hydrazones as Potential Dual Inhibitors of Thioredoxin Reductase and Carbonic Anhydrases.ChemMedChem · 2026Article
- Sappanchalcone suppresses NSCLC by oxidative stress-driven DNA damage and ER stress activation through PIEZO1 modulation.iScience · 2025Article
- Structure-based identification of a non-covalent thioredoxin reductase inhibitor with proven ADMET suitability.Journal of enzyme inhibition and medicinal chemistry · 2025Article
- Article
- Bioactive Clerodane Diterpenoids from the Leaves ofMolecules (Basel, Switzerland) · 2023Article
- Biodereplication of Antiplasmodial Extracts: Application of the Amazonian Medicinal PlantMolecules (Basel, Switzerland) · 2022Article
- Synthesis and SAR Analysis of Novel 4-Hydroxytamoxifen Analogues Based on Their Cytotoxic Activity and Electron-Donor Character.Molecules (Basel, Switzerland) · 2022Article
- Onopordopicrin from the new genusJournal of enzyme inhibition and medicinal chemistry · 2021Article
- Chalcones identify cTXNPx as a potential antileishmanial drug target.PLoS neglected tropical diseases · 2021Article
- Benefits of Ginger and Its Constituent 6-Shogaol in Inhibiting Inflammatory Processes.Pharmaceuticals (Basel, Switzerland) · 2021Review
- A comparative theoretical mechanism on simplified flavonoid derivatives and isoxazolone analogous as Michael system inhibitor.Journal of molecular modeling · 2021Article
- Inhibition of Thioredoxin Reductase by Santamarine Conferring Anticancer Effect in HeLa Cells.Frontiers in molecular biosciences · 2021Article
- Can Selenoenzymes Resist Electrophilic Modification? Evidence from Thioredoxin Reductase and a Mutant Containing α-Methylselenocysteine.Biochemistry · 2020Article
- Molecular targets and anticancer activity of quinoline-chalcone hybrids: literature review.RSC advances · 2020Review
- Effectors of thioredoxin reductase: Brevetoxins and manumycin-A.Comparative biochemistry and physiology. Toxicology & pharmacology : CBP · 2019Article
- Novel hybrids derived from aspirin and chalcones potently suppress colorectal cancerMedChemComm · 2018Article
- Brevetoxin-2, is a unique inhibitor of the C-terminal redox center of mammalian thioredoxin reductase-1.Toxicology and applied pharmacology · 2017Article
- Chalcone: A Privileged Structure in Medicinal Chemistry.Chemical reviews · 2017Review
- Indolin-2-one compounds targeting thioredoxin reductase as potential anticancer drug leads.Oncotarget · 2016Article
- Targeting Thioredoxin Reductase by Parthenolide Contributes to Inducing Apoptosis of HeLa Cells.The Journal of biological chemistry · 2016Article
Corrections and comments
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Authors and funding
12 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
aimsThe role of thioredoxin reductase (TrxR) in tumorigenesis has made it an attractive anticancer target. A systematic approach for development of novel compounds as TrxR inhibitors is currently lacking. Structurally diversified TrxR inhibitors share in common electrophilic propensities for the sulfhydryl groups, among which include the Michael reaction acceptors containing an α,β-unsaturated carbonyl moiety. We aimed to identify features among structurally diversified Michael acceptor-based compounds that would yield a strong TrxR inhibitory character.
resultsStructurally dissimilar Michael acceptor-based natural compounds such as isobutylamides, zerumbone, and shogaols (SGs) were found to possess a poor TrxR inhibitory activity, indicating that a sole Michael acceptor moiety was insufficient to produce TrxR inhibition. The 1,7-diphenyl-hept-3-en-5-one pharmacophore in 3-phenyl-3-SG, a novel SG analog that possessed comparable TrxR inhibitory and antiproliferative potencies as 6-SG, was modified to yield 1,5-diphenyl-pent-1-en-3-one (DPPen) and 1,3-diphenyl-pro-1-en-3-one (DPPro, also known as chalcone) pharmacophores. These Michael acceptor-centric pharmacophores, when substituted with the hydroxyl and fluorine groups, gave rise to analogs displaying a TrxR inhibitory character positively correlated to their antiproliferative potencies. Lead analogs 2,2'-diOH-5,5'-diF-DPPen and 2-OH-5-F-DPPro yielded a half-maximal TrxR inhibitory concentration of 9.1 and 10.5 μM, respectively, after 1-h incubation with recombinant rat TrxR, with the C-terminal selenocysteine residue found to be targeted. INNOVATION: Identification of Michael acceptor-centric pharmacophores among diversified compounds demonstrates that a systematic approach to discover and develop Michael acceptor-based TrxR inhibitors is feasible.
conclusionA strong TrxR inhibitory character correlated to the antiproliferative potency is attributed to structural features that include an α,β-unsaturated carbonyl moiety centered in a DPPen or DPPro pharmacophore bearing hydroxyl and fluorine substitutions.
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