Indolo[3, 2‐c]quinoline G‐Quadruplex Stabilizers: a Structural Analysis of Binding to the Human Telomeric G‐Quadruplex. Issue 5 (26th March 2015)

• Record Type: Journal Article
• Authors: Lavrado, João; Ohnmacht, Stephan A.; Correia, Isabel; Leitão, Clara; Pisco, Sílvia; Gunaratnam, Mekala; Moreira, Rui; Neidle, Stephen; Santos, Daniel J. V. A. dos; Paulo, Alexandra
• Is Part Of: ChemMedChem. Volume 10:Issue 5(2015:May)
• Page Start: 836
• Page End: 849
• Publication Date: 2015-03-26
• Subjects: Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201500067
• Languages: English
• ISSNs: 1860-7179

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>A library of 5‐methylindolo[3, 2‐<italic>c</italic>]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‐11<italic>H</italic>‐indolo[3, 2‐<italic>c</italic>]quinolin‐5‐ium chloride, <bold>3 d</bold>) per G4 unit, in two non‐independent but equivalent binding sites. Molecular dynamics studies suggest that end‐stacking of <bold>3 d</bold> induces a conformational rearrangement in the G4 structure, driving the binding of a second <bold>3 d</bold> ligand to a G4 groove. Modeling studies also suggest that <bold>3 d</bold>, 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 <bold>2 d</bold> (2‐{[3‐(diethylamino)propyl]amino}‐5‐methyl‐11<italic>H</italic>‐indolo[3, 2‐<italic>c</italic>]quinolin‐5‐ium chloride) and <bold>3 d</bold> are 7‐ to 12‐fold more selective for human malignant cell lines than for nonmalignant fibroblasts.</p> </abstract>