title: Improvement of porphyrins for G-quadruplex DNA targeting.
abstract: G-quadruplex nucleic acids are emerging as therapeutic targets for small molecules referred to as small-molecule G-quadruplex ligands. The porphyrin H(2)-TMPyP4 was early reported to be a suitable motif for G-quadruplex DNA recognition. It probably binds to G-quadruplex nucleic acid through π-π stacking with the external G-quartets. We explored chemical modifications of this porphyrin such as insertion of various metal ions in the centre of the aromatic core and addition of bulky substituents that may improve the specificity of the compound toward G-quadruplex DNA. Porphyrin metallation, affording a G4-ligand with two symmetric faces, allowed the conclusion that the presence of an axial water molecule perpendicular to the aromatic plane lowered but did not hamper π-π stacking interactions between the aromatic parts of the ligand on the one hand and the external G-quartet on the other. The charge introduced in the centre of the porphyrin had little influence on binding. Thus, the ionic channel in the centre of G-quadruplex nucleic acids was not found to provide clear additional molecular clues for G-quadruplex nucleic acids targeting by porphyrins tested in the present study. Furthermore, we confirmed the unique G-quadruplex selectivity of a porphyrin modified with four bulky substituents at the meso positions and showed that although the compound is not "drug-like" it was capable of entering cells in culture and mediated some of the typical cellular effects of small-molecule G-quadruplex ligands.
authors.affiliation: CNRS, Laboratoire de Chimie de Coordination, 205 Route de Narbonne, Toulouse Cedex 4, France.
authors.forename: Carmen
authors.initials: C
authors.lastname: Romera
authors.forename: Oriane
authors.initials: O
authors.lastname: Bombarde
authors.forename: Romaric
authors.initials: R
authors.lastname: Bonnet
authors.forename: Dennis
authors.initials: D
authors.lastname: Gomez
authors.forename: Pascal
authors.initials: P
authors.lastname: Dumy
authors.forename: Patrick
authors.initials: P
authors.lastname: Calsou
authors.forename: Jean-Fang
authors.initials: JF
authors.lastname: Gwan
authors.forename: Jung-Hsin
authors.initials: JH
authors.lastname: Lin
authors.forename: Eric
authors.initials: E
authors.lastname: Defrancq
authors.forename: Geneviève
authors.initials: G
authors.lastname: Pratviel
mesh_terms: D001665:Binding Sites; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D031541:Fluorescence Resonance Energy Transfer; D054856:G-Quadruplexes / Q000187:drug effects; D006801:Humans; D008024:Ligands; D008345:Manganese / Q000737:chemistry / Q000378:metabolism; D011166:Porphyrins / Q000737:chemistry* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D019098:Telomerase / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D011166:Porphyrins; C021096:tetra(4-N-methylpyridyl)porphine; D008345:Manganese; D019098:Telomerase