Indolo[3,2-c]quinoline G-Quadruplex Stabilizers: a Structural Analysis of Binding to the Human Telomeric G-Quadruplex

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.

João Lavrado*[a], Stephan A. Ohnmacht [b], Isabel Correia [c], Clara Leitão [b], Sílvia Pisco [b], Mekala Gunaratnam [b], Rui Moreira [a], Stephen Neidle [b], Daniel J. V. A. dos Santos [d], and Alexandra Paulo [a]

[a] J. Lavrado, R. Moreira, A. Paulo Research Institute for Medicines (iMed.ULisboa) Faculty of Pharmacy, Universidade de Lisboa Av. Prof. Gama Pinto, 1649-003 Lisbon (Portugal)
[b] S. A. Ohnmacht, C. Leitão, S. Pisco, M. Gunaratnam, S. Neidle The School of Pharmacy, University College London 29/39 Brunswick Square, London WC1N 1AX (UK)
[c] I. Correia Centro Química Estrutural Instituto Superior Técnico, Universidade de Lisboa Av. Rovisco Pais, 1049-001 Lisboa (Portugal)
[d] D. J. V. A. dos Santos REQUIMTE, Department of Chemistry & Biochemistry Faculty of Sciences, University of Porto R. do Campo Alegre, 4169-007 Porto

http://dx.doi.org/10.1002/cmdc.201500067

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