Development of novel macrocyclic small molecules that target CTG trinucleotide repeats

Julio F. Serrano, Ju Yeon Lee, L. Daniel Curet, Lauren D. Hagler, Sarah E. Bonson, Emma J. Schuster, Steven C. Zimmerman

Research output: Contribution to journalArticle

Abstract

We describe the molecular design, synthesis, and investigation of a series of acridine-triaminotriazine macrocycles that selectively bind to CTG trinucleotide repeats in DNA with minimal nonspecific binding. The limited conformational flexibility enforces the stacking of the triaminotriazine and acridine units. Isothermal titration calorimetry studies and Job plot analyses revealed that the ligands bound to d(CTG) mismatched sites. The acridine and triaminotriazine units were shown to intramolecularly π-stack in aqueous solutions. Compared to a noncyclic analog, the macrocycles showed an almost 10-fold lower cytotoxicity in HeLa cells and up to 4-fold higher transcription inhibition of d(CTG·CAG)74.

Original languageEnglish (US)
Pages (from-to)2978-2984
Number of pages7
JournalBioorganic and Medicinal Chemistry
Volume27
Issue number13
DOIs
StatePublished - Jul 1 2019

Keywords

  • DNA targeting
  • Macrocycle
  • Myotonic dystrophy
  • Rational design
  • Trinucleotide repeats

ASJC Scopus subject areas

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

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