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Intercepted Retro-Nazarov Reaction: Syntheses of Amidino-Rocaglate Derivatives and Their Biological Evaluation as eIF4A Inhibitors.

Abstract
Rocaglates are a family of natural products isolated from the genus Aglaia which possess a highly substituted cyclopenta[b]benzofuran skeleton and inhibit cap-dependent protein synthesis. Rocaglates are attractive compounds due to their potential for inhibiting tumor cell maintenance in vivo by specifically targeting eukaryotic initiation factor 4A (eIF4A) and interfering with recruitment of ribosomes to mRNA. In this paper, we describe an intercepted retro-Nazarov reaction utilizing intramolecular tosyl migration to generate a reactive oxyallyl cation on the rocaglate skeleton. Trapping of the oxyallyl cation with a diverse range of nucleophiles has been used to generate over 50 novel amidino-rocaglate (ADR) and amino-rocaglate derivatives. Subsequently, these derivatives were evaluated for their ability to inhibit cap-dependent protein synthesis where they were found to outperform previous lead compounds including the rocaglate hydroxamate CR-1-31-B.
AuthorsWenhan Zhang, Jennifer Chu, Andrew M Cyr, Han Yueh, Lauren E Brown, Tony T Wang, Jerry Pelletier, John A Porco Jr
JournalJournal of the American Chemical Society (J Am Chem Soc) Vol. 141 Issue 32 Pg. 12891-12900 (08 14 2019) ISSN: 1520-5126 [Electronic] United States
PMID31310112 (Publication Type: 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.)
Chemical References
  • Amidines
  • Antineoplastic Agents
  • Heterocyclic Compounds, 4 or More Rings
  • Eukaryotic Initiation Factor-4A
Topics
  • Amidines (chemical synthesis, pharmacology)
  • Animals
  • Antineoplastic Agents (chemical synthesis, pharmacology)
  • Cell Line, Tumor
  • Drug Screening Assays, Antitumor
  • Eukaryotic Initiation Factor-4A (antagonists & inhibitors)
  • Heterocyclic Compounds, 4 or More Rings (chemical synthesis, pharmacology)
  • Humans
  • Mice
  • Models, Chemical
  • Molecular Structure
  • NIH 3T3 Cells
  • Structure-Activity Relationship

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