Design, synthesis and biological evaluation of a novel class of anticancer agents: Anthracenylisoxazole lexitropsin conjugates

Xiaochun Han, Chun Li, Michael D. Mosher, Kevin C. Rider, Peiwen Zhou, Ronald L. Crawford, William Fusco, Andrzej Paszczynski, Nicholas R. Natale

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

Abstract

The synthesis and in vitro anti-tumor 60 cell lines screen of a novel series of anthracenyl isoxazole amides (AIMs) (While not a strict acronym, the designation AIM is in honor of the memory of Professor Albert I. Meyers.) (22-33) are described. The molecules consist of an isoxazole that pre-organizes a planar aromatic moiety and a simple amide and/or lexitropsin-oligopeptide. The new conjugate molecules were prepared via doubly activated amidation modification of Weinreb's amide formation technique, using SmCl3 as an activating agent which produces improved yields for sterically hindered 3-aryl-4-isoxazolecarboxylic esters. The results of the National Cancer Institute's (NCI) 60 cell line screening assay show a distinct structure activity relationship (SAR), wherein a trend of the highest activity for molecules with one N-methylpyrrole peptide. Evidence consistent with a mechanism of action via the interaction of these compounds with G-quadruplex (G4) DNA and a structural based rational for the observed selectivity of the AIMs for G4 over B-DNA is presented.

Original languageEnglish
Pages (from-to)1671-1680
Number of pages10
JournalBioorganic and Medicinal Chemistry
Volume17
Issue number4
DOIs
StatePublished - Feb 15 2009

Keywords

  • Anthracene
  • Anti-tumor
  • G-quadruplex
  • Isoxazole
  • Pyrrole

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