Imide Condensation as a Strategy for the Synthesis of Core-diversified G-quadruplex Ligands with Anti-cancer and Anti-parasitic Activity

Steve Street, Pablo Peñalver, Michael O'Hagan, Gregory Hollingworth, Juan Carlos Morales, M Carmen Galan*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

Abstract

A facile imide coupling strategy for the one-step preparation of G-quadruplex ligands with varied core chemistries is described. The G-quadruplex stabilization of a library of nine compounds was examined using FRET melting experiments, and CD, UV-Vis, fluorescence and NMR titrations, identifying several compounds that were capable of stabilizing G-quadruplex DNA with interesting selectivity profiles. The best G4 ligand was identified as compound 3 , which was based on a perylene scaffold and exhibited 40-fold selectivity for a telomeric G-quadruplex over duplex DNA. Surprisingly, a tetra-substituted flexible core, compound 11 , also exhibited selective stabilization of G4 DNA over duplex DNA. The anticancer and antiparasitic activity of the library was also examined, with the lead compound 3 exhibiting nanomolar inhibition of T. brucei with 78-fold selectivity over MRC5 cells. The cellular localization of this compound was also studied via fluorescence microscopy. We found that uptake time was time dependant, with localization outside the nucleus and kinetoplast that could be due to strong fluorescence quenching in the presence of small amounts of DNA.

Original languageEnglish
Number of pages11
JournalChemistry - A European Journal
Early online date29 Mar 2021
DOIs
Publication statusE-pub ahead of print - 29 Mar 2021

Keywords

  • G-quadruplexes
  • DNA
  • ligand design approach
  • anti cancer drugs
  • anti parasitic drugs
  • Antiprotozoal agents
  • drug design
  • amphiphiles
  • aggregation

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