Macrocyclic pyridyl polyoxazoles: Structure-activity studies of the aminoalkyl side-chain on G-quadruplex stabilization and cytotoxic activity

Gifty Blankson, Suzanne G. Rzuczek, Cody Bishop, Daniel S. Pilch, Angela Liu, Leroy-Fong Liu, Edmond J. LaVoie, Joseph E. Rice

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5 Citations (Scopus)


Pyridyl polyoxazoles are 24-membered macrocyclic lactams comprised of a pyridine, four oxazoles and a phenyl ring. A derivative having a 2-(dimethylamino)ethyl chain attached to the 5-position of the phenyl ring was recently identified as a selective G-quadruplex stabilizer with excellent cytotoxic activity, and good in vivo anticancer activity against a human breast cancer xenograft in mice. Here we detail the synthesis of eight new dimethylamino-substituted pyridyl polyoxazoles in which the point of attachment to the macrocycle, as well as the distance between the amine and the macrocycle are varied. Each compound was evaluated for selective G-quadruplex stabilization and cytotoxic activity. The more active analogs have the amine either directly attached to, or separated from the phenyl ring by two methylene groups. There is a correlation between those macrocycles that are effective ligands for the stabilization of G-quadruplex DNA (ΔTtran 15.5-24.6 °C) and cytotoxicity as observed in the human tumor cell lines, RPMI 8402 (IC 50 0.06-0.50 μM) and KB3-1 (IC50 0.03-0.07 μM). These are highly selective G-quadruplex stabilizers, which should prove especially useful for evaluating both in vitro and in vivo mechanism(s) of biological activity associated with G-quaqdruplex ligands.

Original languageEnglish
Pages (from-to)11938-11963
Number of pages26
Issue number10
Publication statusPublished - Oct 2013
Externally publishedYes



  • G-quadruplex
  • G-quadruplex ligands
  • G-quadruplex stabilizer
  • Macrocycle
  • Synthesis

ASJC Scopus subject areas

  • Organic Chemistry
  • Medicine(all)

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