Anthracene-terpyridine metal complexes as new G-quadruplex DNA binders.
The formation of quadruple-stranded DNA induced by planar metal complexes has particular interest in the development of novel anticancer drugs. This is especially relevant for the inhibition of telomerase, which plays an essential role in cancer cell immortalization and is overexpressed in ca. 85-90% of cancer cells. Moreover, G-quadruplexes also exist in other locations in the human genome, namely oncogene promoter regions, and it has been hypothesized that they play a regulatory role in gene transcription. Herein we report a series of new anthracene-containing terpyridine ligands and the corresponding Cu(II) and Pt(II) complexes, with different linkers between the anthracenyl moiety and the terpyridine chelating unit. The interaction of these ligands and metal complexes with different topologies of DNA was studied by several biophysical techniques. The Pt(II) and Cu(II) complexes tested showed affinity for quadruplex-forming sequences with a good selectivity over duplex DNA. Importantly, the free ligands do not have significant affinity for any of the DNA sequences used, which shows that the presence of the metal is essential for high affinity (and selectivity). This effect is more evident in the case of the Pt(II) complexes. Moreover, the presence of a longer linker between the chelating terpyridine unit and the anthracene moiety enhances the interaction with G-quadruplex-forming sequences. We further evaluated the ability of the Cu(II) complexes to interact with, and stabilize G-quadruplex containing regions in oncogene promoters via a polymerase stop assay. These studies indicated that the metal complexes are able to induce G-quadruplex formation and stop polymerase activity.
Centro de Ciências e Tecnologias Nucleares (C(2)TN), Instituto Superior Técnico, Universidade de Lisboa, Portugal. Electronic address: sofia.gama@uni-jena.de.
Sofia
S
Gama
Centro de Ciências e Tecnologias Nucleares (C(2)TN), Instituto Superior Técnico, Universidade de Lisboa, Portugal.
Inês
I
Rodrigues
Centro de Ciências e Tecnologias Nucleares (C(2)TN), Instituto Superior Técnico, Universidade de Lisboa, Portugal.
Filipa
F
Mendes
Centro de Ciências e Tecnologias Nucleares (C(2)TN), Instituto Superior Técnico, Universidade de Lisboa, Portugal.
Isabel C
IC
Santos
Dipartimento di Scienze e Innovazione Tecnologica, Università del Piemonte Orientale "Amedeo Avogadro", Alessandria, Italy.
Elisabetta
E
Gabano
Department of Chemistry, Imperial College London, London SW7 2AZ, UK.
Beata
B
Klejevskaja
Department of Chemistry, Imperial College London, London SW7 2AZ, UK.
Jorge
J
Gonzalez-Garcia
Dipartimento di Scienze e Innovazione Tecnologica, Università del Piemonte Orientale "Amedeo Avogadro", Alessandria, Italy.
Mauro
M
Ravera
Department of Chemistry, Imperial College London, London SW7 2AZ, UK.
Ramon
R
Vilar
Centro de Ciências e Tecnologias Nucleares (C(2)TN), Instituto Superior Técnico, Universidade de Lisboa, Portugal.
António
A
Paulo
D000873:Anthracenes / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry*; D001665:Binding Sites; D002413:Cations, Divalent; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry*; D003300:Copper / Q000737:chemistry; D018360:Crystallography, X-Ray; D031541:Fluorescence Resonance Energy Transfer; D015870:Gene Expression; D006801:Humans; D009841:Oligonucleotides / Q000737:chemistry; D010984:Platinum / Q000737:chemistry; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011725:Pyridines / Q000737:chemistry*; D012996:Solutions
D000873:Anthracenes; D000970:Antineoplastic Agents; D002413:Cations, Divalent; D056831:Coordination Complexes; D009841:Oligonucleotides; D016271:Proto-Oncogene Proteins c-myc; D011725:Pyridines; D012996:Solutions; D010984:Platinum; D003300:Copper
Copper complexes; DNA interaction; G-quadruplex; Platinum complexes; Terpyridine derivatives; c-myc