Indolo[3,2-c]quinoline G-quadruplex stabilizers: A structural analysis of binding to the human telomeric G-quadruplex

João Lavrado, Stephan A. Ohnmacht, Isabel Correia, Clara Leitão, Sílvia Pisco, Mekala Gunaratnam, Rui Moreira, Stephen Neidle, Daniel J.V.A.Dos Santos, Alexandra Paulo

Research output: Contribution to journalArticlepeer-review

25 Citations (Scopus)

Abstract

A library of 5-methylindolo[3,2-c]quinolones (IQc) with various substitution patterns of alkyldiamine side chains were evaluated for G-quadruplex (G4) binding mode and efficiency. Fluorescence resonance energy transfer melting assays showed that IQcs with a positive charge in the heteroaromatic nucleus and two weakly basic side chains are potent and selective human telomeric (HT) and gene promoter G4 stabilizers. Spectroscopic studies with HT G4 as a model showed that an IQc stabilizing complex involves the binding of two IQc molecules (2,9-bis{[3-(diethylamino)propyl]amino}-5-methyl-11H-indolo[3,2-c]quinolin-5-ium chloride, 3 d) per G4 unit, in two non-independent but equivalent binding sites. Molecular dynamics studies suggest that end-stacking of 3 d induces a conformational rearrangement in the G4 structure, driving the binding of a second 3 d ligand to a G4 groove. Modeling studies also suggest that 3 d, with two three-carbon side chains, has the appropriate geometry to participate in direct or water-mediated hydrogen bonding to the phosphate backbone and/or G4 loops, assisted by the terminal nitrogen atoms of the side chains. Additionally, antiproliferative studies showed that IQc compounds 2 d (2-{[3-(diethylamino)propyl]amino}-5-methyl-11H-indolo[3,2-c]quinolin-5-ium chloride) and 3 d are 7- to 12-fold more selective for human malignant cell lines than for nonmalignant fibroblasts.

Original languageEnglish
Pages (from-to)836-849
Number of pages14
JournalChemMedChem
Volume10
Issue number5
DOIs
Publication statusPublished - 1 May 2015
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Keywords

  • G-quadruplexes
  • antitumor agents
  • cancer
  • indolo[3,2-c]quinolones
  • molecular dynamics

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