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Indolo[3,2‐ c ]quinoline G‐Quadruplex Stabilizers: a Structural Analysis of Binding to the Human Telomeric G‐Quadruplex
Author(s) -
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
Publication year - 2015
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201500067
Subject(s) - chemistry , stereochemistry , stacking , side chain , hydrogen bond , quinoline , g quadruplex , molecule , ligand (biochemistry) , crystallography , dna , receptor , biochemistry , organic chemistry , polymer
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‐11 H ‐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‐11 H ‐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.