Linking of Antitumor trans NHC-Pt(II) Complexes to G-Quadruplex DNA Ligand for Telomeric Targeting.
G-quadruplex structures (G4) are promising anticancerous targets. A great number of small molecules targeting these structures have already been identified through biophysical methods. In cellulo, some of them are able to target either telomeric DNA and/or some sequences involved in oncogene promotors, both resulting in cancer cell death. However, only a few of them are able to bind to these structures G4 irreversibly. Here we combine within the same molecule the G4-binding agent PDC (pyridodicarboxamide) with a N-heterocyclic carbene-platinum complex NHC-Pt already identified for its antitumor properties. The resulting conjugate platinum complex NHC-Pt-PDC stabilizes strongly G-quadruplex structures in vitro, with affinity slightly affected as compared to PDC. In addition, we show that the new conjugate binds preferentially and irreversibly the quadruplex form of the human telomeric sequence with a profile in a way different from that of NHC-Pt thereby indicating that the platination reaction is oriented by stacking of the PDC moiety onto the G4-structure. In cellulo, NHC-Pt-PDC induces a significant loss of TRF2 from telomeres that is considerably more important than the effect of its two components alone, PDC and NHC-Pt, respectively.
Institut de Chimie des Substances Naturelles, CNRS UPR2301, Université Paris-Sud, Université Paris-Saclay , 1, av. de la Terrasse, 91198 Gif-sur-Yvette, France.
Jean-François
JF
Betzer
Institut de Chimie des Substances Naturelles, CNRS UPR2301, Université Paris-Sud, Université Paris-Saclay , 1, av. de la Terrasse, 91198 Gif-sur-Yvette, France.
Frédérick
F
Nuter
Institut de Chimie des Substances Naturelles, CNRS UPR2301, Université Paris-Sud, Université Paris-Saclay , 1, av. de la Terrasse, 91198 Gif-sur-Yvette, France.
Mélanie
M
Chtchigrovsky
CNRS UMR9187/INSERM U1196, Institut Curie, Centre Universitaire Paris XI , Bâtiments 110-112, 91405 Orsay, France.
Florian
F
Hamon
INSERM UMR-S-1007, Université Paris Descartes , 45, rue des Saints Pères, 75270 Paris, France.
Guillaume
G
Kellermann
INSERM UMR-S-1007, Université Paris Descartes , 45, rue des Saints Pères, 75270 Paris, France.
Samar
S
Ali
INSERM UMR-S-1007, Université Paris Descartes , 45, rue des Saints Pères, 75270 Paris, France.
Marie-Ange
MA
Calméjane
INSERM UMR-S-1007, Université Paris Descartes , 45, rue des Saints Pères, 75270 Paris, France.
Sylvain
S
Roque
Laboratoire de Toxicologie Biologique, Hôpital Lariboisière , 2 rue Ambroise Paré, 75475 Paris, France.
Joël
J
Poupon
Institut de Chimie des Substances Naturelles, CNRS UPR2301, Université Paris-Sud, Université Paris-Saclay , 1, av. de la Terrasse, 91198 Gif-sur-Yvette, France.|Université Paris-Sud d'Innovation Thérapeutique , 5 rue J.B. Clément, 92290 Châtenay-Malabry, France.
Thierry
T
Cresteil
CNRS UMR9187/INSERM U1196, Institut Curie, Centre Universitaire Paris XI , Bâtiments 110-112, 91405 Orsay, France.
Marie-Paule
MP
Teulade-Fichou
Institut de Chimie des Substances Naturelles, CNRS UPR2301, Université Paris-Sud, Université Paris-Saclay , 1, av. de la Terrasse, 91198 Gif-sur-Yvette, France.
Angela
A
Marinetti
CNRS UMR9187/INSERM U1196, Institut Curie, Centre Universitaire Paris XI , Bâtiments 110-112, 91405 Orsay, France.|INSERM UMR-S-1007, Université Paris Descartes , 45, rue des Saints Pères, 75270 Paris, France.
Sophie
S
Bombard
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D054856:G-Quadruplexes / Q000187:drug effects*; D006801:Humans; D008024:Ligands; D009944:Organoplatinum Compounds / Q000737:chemistry* / Q000494:pharmacology*; D021381:Protein Transport / Q000187:drug effects; D013237:Stereoisomerism; D016615:Telomere / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D035341:Telomeric Repeat Binding Protein 2 / Q000378:metabolism
D000970:Antineoplastic Agents; D008024:Ligands; D009944:Organoplatinum Compounds; C569970:Pt-NHC complex; D035341:Telomeric Repeat Binding Protein 2; D004247:DNA