title: Indolo[3,2-c]quinoline G-quadruplex stabilizers: a structural analysis of binding to the human telomeric G-quadruplex.
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.
authors.affiliation: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon (Portugal). jplavrado@ff.ulisboa.pt.
authors.forename: João
authors.initials: J
authors.lastname: Lavrado
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Ohnmacht
authors.forename: Isabel
authors.initials: I
authors.lastname: Correia
authors.forename: Clara
authors.initials: C
authors.lastname: Leitão
authors.forename: Sílvia
authors.initials: S
authors.lastname: Pisco
authors.forename: Mekala
authors.initials: M
authors.lastname: Gunaratnam
authors.forename: Rui
authors.initials: R
authors.lastname: Moreira
authors.forename: Stephen
authors.initials: S
authors.lastname: Neidle
authors.forename: Daniel J V A Dos
authors.initials: DJ
authors.lastname: Santos
authors.forename: Alexandra
authors.initials: A
authors.lastname: Paulo
mesh_terms: D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D054856:G-Quadruplexes / Q000187:drug effects*; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013050:Spectrometry, Fluorescence; D013329:Structure-Activity Relationship; D016615:Telomere / Q000187:drug effects
chemical_list: D007211:Indoles; D011804:Quinolines
keywords: G-quadruplexes; antitumor agents; cancer; indolo[3,2-c]quinolones; molecular dynamics