ABSTRACT
Template-assembled synthetic G-quartet (TASQ) has been reported recently as a G-quadruplex ligand interacting with DNA according to an unprecedented, nature-inspired 'like likes like' approach, based on the association between two G-quartets, one being native (quadruplex) and the other one artificial (ligand). Herein, a novel TASQ-based ligand is designed, synthesized and its quadruplex-recognition properties are evaluated in vitro: PorphySQ (for porphyrin-templated synthetic G-quartet) displays enhanced quadruplex recognition properties as compared to the very first reported prototype (DOTASQ, for DOTA-templated synthetic G-quartet), since the porphyrin template insures a more stable intramolecular G-quartet fold due to self-stabilizing interactions that may take place intramolecularly between the porphyrin ring and the formed G-quartet.
Subject(s)
G-Quadruplexes , Porphyrins/chemistry , Hydrogen Bonding , Ligands , Models, MolecularABSTRACT
Three-way junction DNA (TWJ-DNA, also known as 3WJ-DNA) is an alternative secondary DNA structure comprised of three duplex-DNAs that converge towards a single point, termed the branch point. This point is characterized by unique geometrical properties that make its specific targeting by synthetic small-molecules possible. Such a targeting has already been demonstrated in the solid state but not thoroughly biophysically investigated in solution. Herein, a set of simple biophysical assays has been developed to identify TWJ-specific small-molecule ligands; these assays, inspired by the considerable body of work that has been reported to characterize the interactions between small-molecules and other higher-order DNA (notably quadruplex-DNA), have been calibrated with a known non-specific DNA binder (the porphyrin TMPyP4) and validated via the study of a small series of triazacyclononane (TACN) derivatives (metal-free or not) and the identification of a fairly-affinic and exquisitely TWJ-selective candidate (a TACN-quinoline construct named TACN-Q).
Subject(s)
DNA/chemistry , G-Quadruplexes , Models, Molecular , Small Molecule Libraries/chemical synthesis , Aza Compounds/chemical synthesis , Aza Compounds/metabolism , DNA/metabolism , Fluorescence Resonance Energy Transfer , Kinetics , Ligands , Metals/metabolism , Piperidines/chemical synthesis , Piperidines/metabolism , Porphyrins/chemical synthesis , Porphyrins/metabolism , Quinolines/chemical synthesis , Quinolines/metabolism , Small Molecule Libraries/metabolism , Solutions , Spectrum Analysis , Thermodynamics , Transition TemperatureABSTRACT
An efficient route, starting from but-3-en-1,2-diol, is described to synthesize racemic diastereoisomeric (5-ethoxy-4-vinyl-2,5-dihydrofuran-2-yl) methanol derivatives. Acyclic enyne intermediates having the alkyne moiety directly connected to the asymmetric carbon atom of an acetal were obtained in two steps. These reactive substrates were then subjected to ruthenium-catalyzed enyne metathesis to produce the target compounds in racemic form. The relative configurations were determined by NOE proton NMR experiments. Similar strategy starting from (2S)-but-3-en-1,2-diol was proposed to provide pure enantiomers.
