Porphyrin derivatives for telomere binding and telomerase inhibition.
The capacity of G-quadruplex ligands to stabilize four-stranded DNA makes them able to inhibit telomerase, which is involved in tumour cell proliferation. A series of cationic metalloporphyrin derivatives was prepared by making variations on a meso-tetrakis(4-N-methyl-pyridiniumyl)porphyrin skeleton (TMPyP). The DNA binding properties of nickel(II) and manganese(III) porphyrins were studied by surface plasmon resonance, and the capacity of the nickel porphyrins to inhibit telomerase was tested in a TRAP assay. The nature of the metal influences the kinetics (the process is faster for Ni than for Mn) and the mode of interaction (stacking or external binding). The chemical alterations did not lead to increased telomerase inhibition. The best selectivity for G-quadruplex DNA was observed for Mn-TMPyP, which has a tenfold preference for quadruplex over duplex.
Dixon
Isabelle M
IM
Laboratoire de Chimie de Coordination, CNRS UPR 8241, 205 route de Narbonne, 31077 Toulouse Cedex 4, France.
Lopez
Frédéric
F
Estève
Jean-Pierre
JP
Tejera
Agueda M
AM
Blasco
María A
MA
Pratviel
Geneviève
G
Meunier
Bernard
B
D004247:DNA / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D054856:G-Quadruplexes; D006801:Humans; D008345:Manganese / Q000737:chemistry / Q000378:metabolism; D008665:Metalloporphyrins / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D009532:Nickel / Q000737:chemistry / Q000378:metabolism; D021141:Nucleic Acid Amplification Techniques; D020349:Surface Plasmon Resonance; D019098:Telomerase / Q000037:antagonists & inhibitors*; D016615:Telomere / Q000378:metabolism*
D004791:Enzyme Inhibitors; D008665:Metalloporphyrins; D008345:Manganese; D009532:Nickel; D004247:DNA; D019098:Telomerase