DOI: 10.1002/cmdc.201600171
Communications
Efficient Inhibition of Telomerase by Nickel–Salophen
Complexes
Laureline Lecarme+,[a] Enora Prado+,[a] Aurore De Rache+,[b] Marie-Laure Nicolau-Travers,[c]
Gisle Gellon,[a] JØrôme Dejeu,[a] Thomas Lavergne,[a] HØlne Jamet,[a] Dennis Gomez,[c] Jean-
Louis Mergny,[b] Eric Defrancq,[a] Olivier Jarjayes,[a] and Fabrice Thomas*[a]
Four nickel(II)–salophen complexes containing alkyl-imidazoli-
um chains connected at the ortho or meta positions were pre-
pared: N,N’-bis(2-hydroxy-4-methyl-3H-imidazol-1-iumbenzyli-
deneamino)phenylenediamine (1), N,N’-bis(2-hydroxy-3-methyl-
fied, and G4-DNA has been associated with genomic and epi-
genetic instability as well as diseases and cancer phenotypes.[6]
Only recently has their presence in vivo been demonstrated.[7]
Perhaps the most documented biological function of G-quad-
ruplexes concerns telomere homeostasis.[8] Telomeres are spe-
cialized regions of 10–15 kilobases (at birth) for humans, which
are located at the end of chromosomes.[9] While they are
mainly composed of double-stranded DNA, there is a 3’-over-
hanging, single-stranded region of 100–200 nucleotides at the
terminus. This overhang contains several repeats of G3T2A se-
quences, which has the potential to fold into G-quadruplex-
es.[10] Successive DNA replication steps result in erosion of the
telomeres. Once one or more telomere(s) reaches a critical
length the cell no longer divides further and enters into senes-
cence. Telomerase adds copies of telomeric repeats at the
chromosomal terminus.[2] It is transcriptionally repressed in
normal cells, but is overexpressed in more than 85% of tumor
cells, wherein it prevents senescence.[11] It has been shown
that the presence of G-quadruplexes in the 3’-overhanging
region could inhibit telomerase activity.[2] There is thus a dual
goal for the development of selective G-quadruplex binders:
Firstly, they are potential anticancer drugs, in the sense that
they may restore the mortality of tumor cells;[12] secondly, they
are important tools for gaining deeper insight into the roles of
G-quadruplexes in the genomes.
3H-imidazol-1-iumbenzylideneamino)phenylenediamine
(2),
N,N’-bis(2-hydroxy-3-methyl-3H-imidazol-1-iumbenzylideneami-
no)methyl-3H-imidazol-1-iumphenylenediamine (3), and N,N’-
bis(2-hydroxy-4-methyl-3H-imidazol-1-iumbenzylideneamino)-
methyl-3H-imidazol-1-iumphenylenediamine (4). They protect
G-quadruplex DNA (G4-DNA) against thermal denaturation and
show KA values in the range of 7.4105 to 4107 mÀ1 for G4-
DNA models. Complex 4 exhibits an IC50 value of 70 nm for te-
lomerase inhibition.
Since the seminal discovery of the antiparallel double helical
structure of DNA (B-form DNA) it has been shown that this bio-
logical macromolecule can adopt a wide variety of alternative
topologies such as A-DNA, Z-DNA, H-DNA and cruciform DNA.
Four-stranded G-quadruplex DNA (G4-DNA) has been the sub-
ject of intensive investigations over the past few decades.[1]
This topology requires guanine-rich sequences, such as those
found in the telomeric region of eukaryotic chromosomes, as
well as in promoters of some oncogenes.[2,3] G-quadruplexes
are structured into stacked planar G-quartets, each comprising
four guanines held together by Hoogsteen hydrogen bonds.[4]
A physiologically relevant cation (K+ or Na+) is sandwiched be-
tween two consecutive quartets and stabilizes the edifice. The
Several compounds that efficiently target G-quadruplexes
have emerged in the literature over the last decade.[13] The
most representative inorganic compounds that interact with
G4-DNA are metal complexes of porphyrin[14] and salophen[15] li-
gands, provided that they are functionalized by cationic arms.
We recently showed that nickel(II)–salophen complexes func-
tionalized at both para positions by alkylmethylimidazolium
groups[15e] bind strongly and specifically to G-quadruplexes.
They protect G-quadruplex DNA against thermal denaturation
and inhibit telomerase at the sub-micromolar level (IC50 =
700 nm).[15e] Furthermore, the alkylmethylimidazolium groups
confer high water solubility to the compounds. In this study
we investigated four ortho- and meta-functionalized complexes
(1–4, Figure 1). In particular, we found that one of them (com-
plex 4) exhibits a remarkable IC50 value of 70 nm for telomer-
ase inhibition.
biological relevance of G4-DNA has been established:[5]
A
number of natural G4-DNA binding proteins have been identi-
[a] Dr. L. Lecarme,+ Dr. E. Prado,+ G. Gellon, Dr. J. Dejeu, Dr. T. Lavergne,
Dr. H. Jamet, Prof. E. Defrancq, Dr. O. Jarjayes, Prof. F. Thomas
UniversitØ Grenoble Alpes, DØpartement de Chimie MolØculaire,
UMR-5250, 38041 Grenoble Cedex 9 (France)
Fax: (+33)476-51-4836
E-mail: Fabrice.Thomas@ujf-grenoble.fr
[b] Dr. A. De Rache,+ J.-L. Mergny
ARNA laboratory, Inserm U1212, CNRS UMR 5320, Institut EuropØen de
Chimie et Biologie IECB – UniversitØ de Bordeaux, 2 rue Robert Escarpit,
33607 Pessac (France)
[c] M.-L. Nicolau-Travers, Dr. D. Gomez
Institut de Pharmacologie et de Biologie Structurale,
205 Route de Narbonne, 31077 Toulouse Cedex 4 (France)
[+] These authors contributed equally to this work.
Complexes 1–4 were prepared by condensation of the ap-
propriate phenylenediamine[15e] with one equivalent of Ni(OA-
c)2·4H2O and two equivalents of either 3-(4-formyl-3-hydroxy-
benzyl)-1-methylimidazolium chloride (for the synthesis of
1 and 3), or 3-(3-formyl-2-hydroxybenzyl)-1-methylimidazolium
Supporting information and the ORCID identification number(s) for the
ChemMedChem 2016, 11, 1133 – 1136
1133
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