Macrocyclic pyridyl polyoxazoles

Selective RNA and DNA G-quadruplex ligands as antitumor agents

Suzanne G. Rzuczek, Daniel S. Pilch, Angela Liu, Leroy-Fong Liu, Edmond J. Lavoie, Joseph E. Rice

Research output: Contribution to journalArticle

67 Citations (Scopus)

Abstract

The synthesis of a series of 24-membered pyridine-containing polyoxazole macrocycles is described. Seventeen new macrocycles were evaluated for cytotoxic activity against RPMI 8402, KB-3, and KB-3 cell lines that overexpress the efflux transporters MDR1 (KBV-1) and BCRP (KBH5.0). Macrocycles in which the pyridyl-polyoxazole moiety is linked by a 1,3-bis(aminomethyl)phenyl group with a 5-(2-aminoethyl)- (18) or a 5-(2-dimethylaminoethyl)- substituent (19) displayed the greatest cytotoxic potency. These compounds exhibit exquisite selectivity for stabilizing G-quadruplex DNA with no stabilization of duplex DNA or RNA. Compound 19 stabilizes quadruplex mRNA that encodes the cell-cycle checkpoint protein kinase Aurora A to a greater extent than the quadruplex DNA of a human telomeric sequence. These data may suggest a role for G-quadruplex ligands interacting with mRNA being associated with the biological activity of macrocyclic polyoxazoles. Compound 19 has significant in vivo anticancer activity against a human breast cancer xenograft (MDA-MB-435) in athymic nude mice.

Original languageEnglish
Pages (from-to)3632-3644
Number of pages13
JournalJournal of Medicinal Chemistry
Volume53
Issue number9
DOIs
Publication statusPublished - May 13 2010
Externally publishedYes

Fingerprint

G-Quadruplexes
Antineoplastic Agents
Ligands
Nude Mice
KB Cells
Cell Cycle Proteins
Messenger RNA
Cell Cycle Checkpoints
Heterografts
Protein Kinases
RNA
Breast Neoplasms
Cell Line
DNA

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Macrocyclic pyridyl polyoxazoles : Selective RNA and DNA G-quadruplex ligands as antitumor agents. / Rzuczek, Suzanne G.; Pilch, Daniel S.; Liu, Angela; Liu, Leroy-Fong; Lavoie, Edmond J.; Rice, Joseph E.

In: Journal of Medicinal Chemistry, Vol. 53, No. 9, 13.05.2010, p. 3632-3644.

Research output: Contribution to journalArticle

Rzuczek, Suzanne G. ; Pilch, Daniel S. ; Liu, Angela ; Liu, Leroy-Fong ; Lavoie, Edmond J. ; Rice, Joseph E. / Macrocyclic pyridyl polyoxazoles : Selective RNA and DNA G-quadruplex ligands as antitumor agents. In: Journal of Medicinal Chemistry. 2010 ; Vol. 53, No. 9. pp. 3632-3644.
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