Second-generation derivatives of the eukaryotic translation initiation inhibitor pateamine A targeting eIF4A as potential anticancer agents

Woon Kai Low, Jing Li, Mingzhao Zhu, Sai Shilpa Kommaraju, Janki Shah-Mittal, Ken Hull, Jun O. Liu, Daniel Romo

Research output: Contribution to journalArticlepeer-review

Abstract

A series of pateamine A (1) derivatives were synthesized for structure/activity relationship (SAR) studies and a selection of previous generation analogs were re-evaluated based on current information regarding the mechanism of action of these translation inhibitors. Structural modifications in the new generation of derivatives focused on alterations to the C19-C22 Z,E-diene and the trienyl side chain of the previously described simplified, des-methyl, des-amino pateamine A (DMDAPatA, 2). Derivatives were tested for anti-proliferative activity in cell culture and for inhibition of mammalian cap-dependent translation in vitro. Activity was highly dependent on the rigidity and conformation of the macrolide and the functionality of the side chain. The only well tolerated substitutions were replacement of the N,N-dimethyl amino group found on the side chain of 2 with other tertiary amine groups. SAR reported here suggests that this site may be modified in future studies to improve serum stability, cell-type specificity, and/or specificity towards rapidly proliferating cells.

Original languageEnglish (US)
Pages (from-to)116-125
Number of pages10
JournalBioorganic and Medicinal Chemistry
Volume22
Issue number1
DOIs
StatePublished - Jan 1 2014

Keywords

  • DMDAPatA
  • Pateamine A
  • Stille coupling
  • Translation initiation
  • eIF4A

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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