Synthesis and evaluation of 2, 9-disubstituted-1, 10-phenanthroline derivatives as G-quadruplex binders. (1st November 2022)

• Record Type: Journal Article
• Authors: Figueiredo, Joana; Carreira-Barral, Israel; Quesada, Roberto; Mergny, Jean-Louis; Cruz, Carla
• Is Part Of: Bioorganic & medicinal chemistry. Volume 73(2022)
• Publication Date: 2022-11-01
• Subjects: G-quadruplex structures -- 2, 9-disubstituted-1, 10-phenanthroline derivatives -- Biophysical evaluation -- In vitro studies; CD Circular dichroism -- DCM Dichloromethane -- DMSO Dimethylsulfoxide -- FRET Förster Resonance Energy Transfer -- FAM Fluorescein amidites -- FBS Fetal bovine serum -- G4 G-quadruplex -- NHDF Normal human dermal fibroblasts -- MTT 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide -- RPMI Roswell Park Memorial Institute Medium -- SP Streptomycin-penicillin -- TAMRA Tetramethyl rhodamine -- TFA Trifluoracetic acid -- 5′UTR RNA 5′-untranslated regions; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2022.116971
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: G-quadruplex (G4) structures are non-canonical DNA/RNA secondary structures able to form within guanine rich nucleic acids sequences. They are present in several regions of the human genome including gene promoters, untranslated sequences, and telomeres. Due to their biological relevance G4 structures are considered important drug targets, in particular for anticancer therapies, leading to the development of G4 stabilizing small molecules. Telomeric regions have received special attention in this field since they can fold into several distinct intramolecular G-quadruplexes topologies. Herein, we report the synthesis of 2, 9-disubstituted-1, 10-phenanthroline derivatives and their ability to stabilize different intramolecular telomeric G4 sequences. We evaluated ligand-induced stabilization, selectivity and specificity of ligands using Förster Resonance Energy Transfer (FRET) melting experiments and circular dichroism (CD). In addition, we assessed the cytotoxicity of ligands against two cancer cell lines (A549 and H1299) and one healthy cell line (NHDF).