ArticleJournal of medicinal chemistry2020
Synthesis of Guaianolide Analogues with a Tunable α-Methylene-γ-lactam Electrophile and Correlating Bioactivity with Thiol Reactivity.
Article in Journal of medicinal chemistry, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 21 citations in OpenAlex.
- A Predictive Model for Thiol Reactivity ofJournal of medicinal chemistry · 2025Article
- Domino Reactions Enable Zn-Mediated Direct Synthesis of Spiro-Fused 2-Oxindole-α-Methylene-γ-Butyrolactones/Lactams from Isatin Derivatives and 2-(Bromomethyl)acrylates.Molecules (Basel, Switzerland) · 2024Article
- An electrophilic fragment screening for the development of small molecules targeting caspase-2.European journal of medicinal chemistry · 2023Article
- Catalytic aza-Nazarov cyclization reactions to access α-methylene-γ-lactam heterocycles.Beilstein journal of organic chemistry · 2023Article
- Cytotoxicity of phenylpironetin analogs and the metabolic fate of pironetin and phenylpironetin.Bioorganic chemistry · 2022Article
- One-Pot Diastereoselective Synthesis of Pyrrolopiperazine-2,6-diones by a Ugi/Nucleophilic Substitution/N-Acylation Sequence.The Journal of organic chemistry · 2022Article
- Syntheses Based on 3,4α-Epoxy-1,5,7α,6β(H)-guai-10(14),11(13)-dien-6,12-olide.Molecules (Basel, Switzerland) · 2022Article
- Anticancer Targets and Signaling Pathways Activated by Britannin and Related Pseudoguaianolide Sesquiterpene Lactones.Biomedicines · 2021Review
- Function-Oriented and Modular (+/-)-cis-Pseudoguaianolide Synthesis: Discovery of New Nrf2 Activators and NF-κB Inhibitors.Chemistry (Weinheim an der Bergstrasse, Germany) · 2021Article
Corrections and comments
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
Abstract
α-Methylene-γ-lactones are present in ∼3% of known natural products, and compounds comprising this motif display a range of biological activities. However, this reactive lactone limits informed structure-activity relationships for these bioactive molecules. Herein, we describe chemically tuning the electrophilicity of the α-methylene-γ-lactone by replacement with an α-methylene-γ-lactam. Guaianolide analogues having α-methylene-γ-lactams are synthesized using the allenic Pauson-Khand reaction. Substitution of the lactam nitrogen with electronically different groups affords diverse thiol reactivity. Cellular NF-κB inhibition assays for these lactams were benchmarked against parthenolide and a synthetic α-methylene-γ-lactone showing a positive correlation between thiol reactivity and bioactivity. Cytotoxicity assays show good correlation at the outer limits of thiol reactivity but less so for compounds with intermediate reactivity. A La assay to detect reactive molecules by nuclear magnetic resonance and mass spectrometry peptide sequencing assays with the La antigen protein demonstrate that lactam analogues with muted nonspecific thiol reactivities constitute a better electrophile for rational chemical probe and therapeutic molecule design.
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