G-quadruplex vs. duplex-DNA binding of nickel(II) and zinc(II) Schiff base complexes

Article abstract of DOI:10.1016/j.jinorgbio.2016.05.010

Novel nickel(II) (1) and zinc(II) (2) complexes of a Salen-like ligand, carrying a pyrimidine ring on the N,N′ bridge, were synthesized and characterized. Their interaction with duplex and G-quadruplex DNA was investigated in aqueous solution through UV-visible absorption, circular dichroism and viscometry measurements. The results obtained point out that, while the zinc(II) complex does not interact with both duplex and G-quadruplex DNA, the nickel(II) complex 1 binds preferentially to G-quadruplex respect to duplex-DNA, with values of the DNA-binding constants, K_b, 2.6 × 10⁵ M^{- 1} and 3.5 × 10⁴ M^{- 1}, respectively. Molecular dynamics simulations provided an atomic level model of the top-stacking binding occurring between 1 and hTelo (a 22-mer sequence oligonucleotide) in G-quadruplex conformation.

Full text of DOI:10.1016/j.jinorgbio.2016.05.010

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
G-quadruplex vs. duplex-DNA binding of nickel(II) and zinc(II) Schiff base
complexes
Riccardo Bonsignore, Alessio Terenzi, Angelo Spinello, Annamaria Mar-
torana, Antonino Lauria, Anna Maria Almerico, Bernhard K. Keppler,
Giampaolo Barone
PII:
DOI:
Reference:
S0162-0134(16)30133-7
doi: 10.1016/j.jinorgbio.2016.05.010
JIB 9999
To appear in:
Journal of Inorganic Biochemistry
Received date:
Revised date:
Accepted date:
5 February 2016
21 April 2016
13 May 2016
Please cite this article as: Riccardo Bonsignore, Alessio Terenzi, Angelo Spinello,
Annamaria Martorana, Antonino Lauria, Anna Maria Almerico, Bernhard K. Kep-
pler, Giampaolo Barone, G-quadruplex vs.
duplex-DNA binding of nickel(II)
and zinc(II) Schiff base complexes, Journal of Inorganic Biochemistry (2016), doi:
10.1016/j.jinorgbio.2016.05.010
This is a PDF file of an unedited manuscript that has been accepted for publication.
As a service to our customers we are providing this early version of the manuscript.
The manuscript will undergo copyediting, typesetting, and review of the resulting proof
before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that
apply to the journal pertain.

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
ACCEPTED MANUSCRIPT
G-quadruplex vs. duplex-DNA binding of nickel(II) and zinc(II) Schiff
base complexes
Riccardo Bonsignore,a,b Alessio Terenzi,c,d Angelo Spinello,a,b Annamaria Martorana,a Antonino
Lauria,a Anna Maria Almerico,a Bernhard K. Keppler,c,d Giampaolo Barone*a,b
a
Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche, Viale delle
Scienze, Edificio 17, 90128 Palermo, Italy.
b Istituto EuroMediterraneo di Scienza e Tecnologia, Piazzetta Briuccia, 20-21, 90139 Palermo,
Italy.
c
Institute of Inorganic Chemistry, University of Vienna, Waehringerstr. 42, A-1090 Vienna,
Austria.
d
Research Platform “Translational Cancer Therapy Research”, University of Vienna and
Medical University of Vienna, Vienna, Austria.
* Corresponding author: E-mail: giampaolo.barone@unipa.it; Fax: +39 091 596825.
Abstract:
Novel nickel(II) (1) and zinc(II) (2) complexes of a Salen-like ligand, carrying a pyrimidine ring
on the N,N’ bridge, were synthesized and characterized. Their interaction with duplex and G-
quadruplex DNA was investigated in aqueous solution through UV-visible absorption, circular
dichroism and viscometry measurements. The results obtained point out that, while the zinc(II)
complex does not interact with both duplex and G-quadruplex DNA, the nickel(II) complex 1
binds preferentially to G-quadruplex respect to duplex-DNA, with values of the DNA-binding
constants, Kb, 2.6✕105 M-1 and 3.5✕104 M-1, respectively. Molecular dynamics simulations
provided an atomic level model of the top-stacking binding occurring between 1 and hTelo G-
quadruplex.
Keywords: Binding Constant; Circular Dichroism; Computational Chemistry; DNA G-
quadruplex, Nickel; Zinc
1

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
ACCEPTED MANUSCRIPT
1. INTRODUCTION
First row metal complexes of Schiff base ligands possess interesting and tunable DNA-binding
properties [1–3], ranging from DNA-intercalation to groove binding, depending on the size and
shape of the ligand and on the nature of the coordinated metal ion.
In the last 10 years, our research group has investigated on several transition metal complexes
of ligands generated by the condensation of a chosen diamine and a modified salicylaldehyde,
within what is known as Metal-Salen chemistry [4]. In particular, by changing the diamine and
the central ion we obtained compounds with different affinity for DNA and with diverse binding
modes. For example, an iron(III) Salen complex shows groove binding properties [5], while
nickel(II), copper(II) and zinc(II) Salphen derivatives are DNA intercalators [6–8]. The zinc(II)-
Salphen-like complex showed interesting photochemical properties, being the fluorescent
emission of the photooxydized product drastically quenched by the DNA-intercalation process
[9–11].
Computational chemistry has played an important role in our research, for supporting the
interpretation of solution absorption and emission spectra, and for providing atomistic models
for the DNA-binding mechanism [10–13].
Recently, also inspired by the work of Vilar, Aldrich-Wright, Neidle, and coworkers [14–17]
on similar metal complexes, our interest has moved toward the search for novel Schiff base
complexes as selective G-quadruplex binders [13].
G-quadruplexes (G4) are non canonical secondary DNA structures, arising from guanine-rich
sequences, in which four guanines are linked by Hoogsteen hydrogen bonds thus creating tetrads
that are stabilized both by π-π stacking interactions between them, and by the presence of a
cation (usually K+) coordinated to O6 of the guanines. Recently, these structures have been
found to occur in human cells, especially in guanine-rich sequences found in telomeric and in
2

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
ACCEPTED MANUSCRIPT
proto-oncogene promoting regions of the polynucleotide [18,19] such as c-Kit, KRAS, PDGF-A
and c-Myc [20–22]. It has been proposed that G4 folding has a regulatory mechanism for the
transcription of these genes, whose expression is associated with the occurrence of cancer and
that their stabilization as G4-DNA by designed molecules might lead to block their transcription
and have remarkable activity in anticancer therapy [20]. Moreover, human telomeric DNA is
known to shorten during cells replications until a limit length when cells enter senescence and
induce their own apoptosis. Nevertheless, some cells as stem ones overcome the telomeric-
shortening induced apoptosis by means of a reverse transcriptase enzyme, namely the
telomerase, capable to catalyse the elongation of the telomeres. Unluckily, its overexpression in
cancer cells grants them infinite proliferative capabilities [23]. In such a context, the stabilization
of the telomeres as guanine quadruplex by means of small binders could inhibit telomerase
activity and therefore become a powerful strategy for anticancer treatments [13,15]. Notably, for
the structural differences between G-quadruplex and duplex-DNA, a molecule that exhibit a
selective interaction with G4 rather than duplex-DNA, might have less toxic effects and might
also be more suitable for treatments.
As a continuation of our research in this field, here we report on the synthesis of two novel
nickel(II) (1) and zinc(II) (2) complexes of a Salen-like derivative, presenting a pyrimidine
moiety on the N,N’ bridge (see Scheme 1) and on the study of their binding properties with both
duplex and G-quadruplex DNA.
2. MATERIALS AND METHODS
General. Solvents and reagents (reagent grade) were all commercially available and used
without further purification. The 5-(triethylammoniummethyl)salicylaldehyde chloride ligand
was prepared from 5-chloromethyl salicylaldehyde and triethylamine in tetrahydrofuran, as
recently reported [12]. 1H and 13C NMR spectra were recorded in DMSO-d6 solution, with TMS
as an internal reference, on a Bruker Avance 500 and 125 MHz NMR spectrometer. Mass
3