title: Porphyrin-based design of bioinspired multitarget quadruplex ligands.
abstract: Secondary nucleic acid structures, such as DNA and RNA quadruplexes, are potential targets for cancer therapies. Ligands that interact with these targets could thus find application as anticancer agents. Synthetic G-quartets have recently found numerous applications, including use as bioinspired G-quadruplex ligands. Herein, the design, synthesis and preliminary biophysical evaluation of a new prototype multitarget G-quadruplex ligand, (PNA)PorphySQ, are reported, where peptidic nucleic acid guanine ((PNA)G) was incorporated in the porphyrin-templated synthetic G-quartet (PorphySQ). Using fluorescence resonance energy transfer (FRET)-melting experiments, PorphySQ was shown to possess enhanced quadruplex-interacting properties thanks to the presence of four positively charged (PNA)G residues that improve its electrostatic interactions with the binding site of both DNA and RNA quadruplexes (i.e., their negatively charged and accessible G-quartets), thereby making (PNA)PorphySQ an interesting prototype of a multitarget ligand. Both the chemical stability and water solubility of (PNA)PorphySQ are improved over the non-PNA derivative (PorphySQ), which are desirable properties for drug development, and while improvements remain to be made, this ligand is a promising lead for the further development of multitarget G-quadruplex ligands.
authors.affiliation: Institut de Chimie Moléculaire, Université de Bourgogne (ICMUB), CNRS UMR6302, Dijon (France).
authors.forename: Aurélien
authors.initials: A
authors.lastname: Laguerre
authors.forename: Nicolas
authors.initials: N
authors.lastname: Desbois
authors.forename: Loic
authors.initials: L
authors.lastname: Stefan
authors.forename: Philippe
authors.initials: P
authors.lastname: Richard
authors.forename: Claude P
authors.initials: CP
authors.lastname: Gros
authors.forename: David
authors.initials: D
authors.lastname: Monchaud
mesh_terms: D001665:Binding Sites; D004247:DNA / Q000187:drug effects; D054856:G-Quadruplexes / Q000187:drug effects*; D006147:Guanine / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D020135:Peptide Nucleic Acids / Q000737:chemistry; D011166:Porphyrins / Q000737:chemistry*; D012313:RNA / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D020135:Peptide Nucleic Acids; D011166:Porphyrins; D006147:Guanine; D012313:RNA; D004247:DNA
keywords: biomimetic ligands; guanine; porphyrins; quadruplex ligands; quadruplexes; synthetic G-quartets