Synthesis of Guaianolide Analogues with a Tunable α-Methylene-γ-lactam Electrophile and Correlating Bioactivity with Thiol Reactivity

Paul A. Jackson, Henry A.M. Schares, Katherine F.M. Jones, John C. Widen, Daniel P. Dempe, Francois Grillet, Matthew E. Cuellar, Michael A. Walters, Daniel A. Harki, Kay M. Brummond

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)14951-14978
Number of pages28
JournalJournal of medicinal chemistry
Volume63
Issue number23
DOIs
StatePublished - Dec 10 2020

Bibliographical note

Funding Information:
This work was supported by the NIH (R01-GM110129 to DAH) and the University of Pittsburgh. Funding for NMR instrumentation used for ALARM NMR assay was provided by the UMN Office of the Vice President for Research, UMN Medical School, UMN College of Biological Science, NIH, NSF and the Minnesota Medical Foundation. Protein MS was performed at the Analytical Biochemistry Core Facility of the UMN Masonic Cancer Center, which is supported by the NIH (P30-CA77598). KFMJ was supported by the National Science Foundation Graduate Research Fellowship Program.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

Fingerprint Dive into the research topics of 'Synthesis of Guaianolide Analogues with a Tunable α-Methylene-γ-lactam Electrophile and Correlating Bioactivity with Thiol Reactivity'. Together they form a unique fingerprint.

Cite this