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Coordination Chemistry Reviews xxx (2013) xxxxxx

Contents lists available at SciVerse ScienceDirect

Coordination Chemistry Reviews


journal homepage: www.elsevier.com/locate/ccr

Review

DNA-binding of nickel(II), copper(II) and zinc(II) complexes:


Structureafnity relationships
Giampaolo Barone a,b, , Alessio Terenzi a , Antonino Lauria a , Anna Maria Almerico a ,
Jos M. Leal c , Natalia Busto c , Begona Garca c
a
Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche, Universit di Palermo, Viale delle Scienze, Parco dOrleans II, Edicio 17,
90128 Palermo, Italy
b
Istituto EuroMediterraneo di Scienza e Tecnologia, Via Emerico Amari 123, 90139 Palermo, Italy
c
Departamento de Qumica, Universidad de Burgos, Plaza Misael Banuelos, 09001 Burgos, Spain

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
1.1. State of the art and scope of the review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
1.2. Binding modes of DNAdrug interaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
1.2.1. Covalent binding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
1.2.2. Non-covalent binding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
1.2.3. Interaction of metal ions and metal complexes with nucleic acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
1.3. Techniques used to monitor the metal complex-DNA binding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2. Nickel(II), copper(II) and zinc(II) DNA-binding complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.1. Schiff base ligands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.2. Other ligands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3. Rationalization of the literature results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.1. Geometry and electronic structure of the metal complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.2. Covalent and/or non-covalent interactions? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

a r t i c l e i n f o a b s t r a c t

Article history: Nickel(II), copper(II) and zinc(II) complexes with the same ligands normally display analogous coordi-
Received 29 November 2012 nation geometry and binding mode toward DNA. However, although qualitatively alike in structure and
Received in revised form 11 February 2013 properties, different DNA-binding ability has often been observed. This review surveys the most recent
Accepted 19 February 2013
examples of binding of the three metal ions complexed with monodentate and chelating bidentate to
Available online xxx
tetradentate ligands to DNA. An attempt has also been made to rationalize the observed trend in the
values of the intrinsic DNA-binding constant, Kb , in terms of structural and chemical features.
Keywords:
2013 Elsevier B.V. All rights reserved.
Binding constant
Copper
DNA
Nickel
Zinc

1. Introduction

1.1. State of the art and scope of the review

Corresponding author at: Dipartimento di Scienze e Tecnologie Biologiche,


Metal complexes constitute an important class of compounds
Chimiche e Farmaceutiche, Universit di Palermo, Viale delle Scienze, Parco
endowed with biological interest. This type of compounds is widely
dOrleans II, Edicio 17, 90128 Palermo, Italy. Tel.: +39 091 23897973;
fax: +39 091590015. used in Medicine as a contrast agent in Image Magnetic Resonance
E-mail address: giampaolo.barone@unipa.it (G. Barone). (MRI), in Radiopharmaceuticals, in the treatment of arthritis, ulcers

0010-8545/$ see front matter 2013 Elsevier B.V. All rights reserved.
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and in cancer chemotherapy [15]. In spite of the fact that rel- Among the metal ions regarded as coordination centers of
atively few coordination compounds have been implemented as potential anticancer agents, platinum and ruthenium ions, are
drugs (partially due to the scant interest of the pharmaceutical the most widely investigated up to now [7,13]. However, there
industry to switch from organic to inorganic synthetic procedures), is a growing interest in the synthesis of cheaper rst-row tran-
these compounds are more and more used to disclose the struc- sition metal complexes as efcient DNA binders with potential
tural behaviour and nucleic acid functions as marker agents and cytotoxic activity [3944]. With this in mind, in this review the
promoters in anchoring processes [6]. attention is focused primarily on the research concerning the DNA-
The observation in 1964 of the cis-Platinum [Pt(NH3 )2 Cl2 ] ability binding with nickel(II), copper(II) and zinc(II) complexes, an issue
to suppress the cell division and its ulterior clinical use in the treat- extensively investigated. The three metal ions are present as essen-
ment of a range of cancers with outstanding results [7], suddenly tial elements in the biological intracellular environment of living
prompted a growing interest in the development of metal-based organisms [4548]. Together with iron, they are the most abundant
drugs [8,9]. Compounds of the cis-Platinum family, carboplatinum trace elements present in biological systems and are contained in
and similar complexes, that may attack covalently the nucleobases, several metalloproteins [47,49,50]. These metal ions are nowadays
have long been the object of an exhaustive survey [1012]. present in several inorganic pharmaceuticals used as drugs against
Other active areas of research are focused on the development of a variety of diseases, ranging from antibacterial and antifungal to
new metallodrugs having the ability to interact with DNA. Among anticancer applications [5154]. Additionally, their complexes with
these, organometallic ruthenium complexes have a great deal of planar heterocyclic ligands are efcient DNA-binders and display
promise [410,13]. Over the last few years, a large number of stronger afnity with DNA than the corresponding free ligands
contributions on the synthesis, cytotoxicity and DNA binding of [18,5557]. They can interact with DNA by different modes of
this class of compounds have been published, and some of them binding. In the presence of oxidizing or reducing agents, these com-
(like NAMI-A or KP1019) have undergone clinical trials [11]. Other pounds are able to cleave it [58]. Research on the DNA cleavage
important families are those of RM175 [14] or RAPTA-T [15,16] syn- by synthetic metal complexes has aroused considerable interest
thesized by Peter J. Sadler and Paul J. Dyson groups, respectively. because of their efcacy as anti-tumor agents [58]. Interestingly,
Both families consist of Ru(II) arene complexes that have shown the correlation between DNA-binding and cytotoxic activity against
in vitro and in vivo anticancer activity [15]. cancer cells is still a crucial step in the search for new anticancer
Transition metal complexes offer two peculiar advantages as drugs [51,52,5967]. The only limitation to their application as
DNA-binding agents [17]. First and foremost, transition metals drugs could stem from the lower thermodynamic and/or kinetic
centers are particularly attractive moieties for reversible recogni- stability of their metal complexes [68] compared with the anal-
tion of nucleic acids research because they exhibit well-dened ogous ruthenium(II) or platinum(II) partners [59,69]; however,
coordination geometries. Moreover, they often possess distinctive this may depend strongly on the nature of the coordinating
electrochemical or photophysical properties, thus enhancing the ligands.
functionality of the binding agent [15]. Indeed, these characteris- Subtle differences in size and shape of octahedral complexes
tics have prompted metal complexes to be used in a wide range of with same ligands, may alter dramatically the DNA afnity and
applications, from uorescent markers to DNA foot-printing agents, selectivity [70]. In fact, the difference in strength of binding with
to electrochemical probes [18]. DNA of nickel(II), copper(II) and zinc(II), bearing the same coordi-
The interaction between DNA and metal complexes, in aque- nating ligands, as well as the qualitative and quantitative difference
ous solution at neutral pH, is usually monitored as a function of in the spectral features, can be put forward primarily to the dif-
the metal complex-DNA molar ratio, by a number of experimental ferent electronic structure of the three metal compounds, that is,
techniques (see Section 1.3), which may provide indirect evidence the different occupation of the 3d orbitals of the metal and their
for the interaction, but not atomic-level structural details. Delicate different molecular geometry, the overall charge being the same.
and expensive experiments are necessary to detect structural fea- Furthermore, the three metals are contiguous in the 4rd row of the
tures, for example involving application of X-ray crystallography Periodic Table. The unequal number of d electrons has been used
or nuclear magnetic resonance (NMR), and use of small synthetic to explain, for instance, the observed difference in magnetic, spec-
oligonucleotides [1922]. In fact, knowledge of structural and troscopic, redox and structural properties between their analogous
energy features about the interaction between metal complexes compounds [71,72].
and DNA is of key importance, because they can afford an atomistic Particular attention has been devoted to transition metal com-
model to interpret macroscopic properties related to such phe- plexes endowed with planar aromatic side groups, which can bind
nomenon. For this reason, several computational approaches have with DNA by both metal ion coordination and intercalation of the
been proposed as complementary tools to look into moleculeDNA aromatic moiety [73]. This requirement is met particularly when
interactions [2338]. Quantum chemical calculations are more and the metal complex has empty coordination sites available or labile
more used to obtain structural details of the interaction. Further- ligands, which can be replaced by O or N donor atoms of the DNA
more, the observed qualitative and quantitative difference between bases. Liu and Sadler [73] and Dyson [74] have reported recently
the interaction mechanisms can be rationalized on the basis of the that metal complexes able to bind with DNA both covalently and
nature of the coordinated metal ion and the overall interaction non-covalently, normally display enhanced biological activity com-
energy. pared with non-covalent binders. Since unsaturated coordination
It is not always easy to discern between different interaction nickel(II), copper(II) and zinc(II) complexes often manifest remark-
mechanisms, and the differentiation between multiple binding able anti-proliferative activity against cancer cell lines [7579], it
sites and sequence selectivity still remains under debate. In this is reasonable to hypothesize that in such cases they can interact
regard, the intrinsic binding constants, Kb , often determined by with DNA also by covalent binding with the N and/or O atoms of
electrochemical or spectroscopic techniques such as absorption or the DNA bases.
uorescence spectrophotometric titrations, may prove the occur- In this context, it is quite surprising that neither qualitative
rence of a marked interaction with DNA. Although affected to some nor quantitative comparison of the DNA-binding strength of the
extent by the conditions, in particular the ionic strength of the three title metal(II) complexes bearing the same ligand have been
medium, intrinsic DNA-binding constants constitute a valuable reported in the literature hitherto. With these precedents in mind,
indicator of the afnity of metal compounds to the DNA macro- this review aims to summarize the intrinsic DNA-binding constants
molecule. of analogous nickel(II), copper(II) and zinc(II) complexes, with

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A B
NH2
NH2
HN
N O N
N
NH3
O N N 5'
OH3N Pt N N
R
- P
O O
O
O- H H N
HN
H H
OH H
H2N N N DNA
backbone
3'
R

Fig. 1. (A) Reacting sites in which external agents may covalently bind the nucleotides: metal binding sites (in red); alkylation and nitrosation reaction sites (in blue). (B)
Chemical structure of the adduct formed by cross-linking of cis-Platinum with two guanines of the same strand, d (GpG).

particular emphasis on the most recent literature results. Addition- 1.2.1. Covalent binding
ally, an attempt is made to rationalize the observed trends on the Although the covalent binding of metal complexes with nucleic
basis of the coordination chemistry properties of the complexes acids is in general kinetically controlled, the rate and metallation
described. site can be conveniently modulated by the initial reversible non-
covalent binding (pre-association). As the DNA is a polyanion, the
pre-association step is particularly signicant if the metal complex
1.2. Binding modes of DNAdrug interaction is cationic in nature. The covalent binding is irreversible and gives
way to adduct species that prevent from cell replication. Fig. 1A
Learning of the fundamentals of the drugnucleic acid inter- shows the reacting sites in which the agents may form adducts with
action requires previous answer to questions such as why? How the nucleotides, whereas Fig. 1B shows the binding of the antitu-
much? Where? To what extent? To get a detailed view on this issue, mour agent cis-platinum to the N7 site of two guanines and to the
knowledge of the kinetics, mechanism and energy involved in the DNA chain, respectively.
DNAdrug interaction is necessary [80]. Hence, understanding of
the mechanisms by which the drugs interact with nucleic acids and 1.2.2. Non-covalent binding
their correlation with biological effects has been the object of great Many of the drugs used nowadays as anticancer, antiviral
attention. In fact, comprehension of this interaction is a key objec- pharmaceuticals or antibiotics exert their effects by a reversible
tive in the study of diseases caused by pathogen agents as well as all interaction with the nucleic acids; intercalation and groove tting
types of genetic diseases [81]. As an outcome of these researches, are the main modes of non-covalent interaction (see e.g. Fig. 2
the design of structure-based drugs and its subsequent production [87,88]). For this reason, it is important to discern whether their
has undergone a notable progress [81]. effect is external or, alternatively, they function as intercalators
Regardless of the particular type, at large drugnucleic acid or groove binders under the pH, temperature and ionic strength
interactions induce changes in the nucleic acid structure that may solvent conditions [89,90].
result in conformational alterations as well as loss, addition or Intercalation (Fig. 2A) consists of the insertion of the drug
substitution of the bases, thus modifying the DNA sequence and between neighbour pairs of bases [91], thus unwinding the strands
affecting the faithfulness of the genetic message. These changes to -stack between two base-pairs. This process entails distortion
may inhibit the synthesis of proteins (inhibition of the gene expres- of the conformation of the DNA backbone and therefore interfer-
sion) or give rise to protein synthesis with a modied structure ence of the proteinDNA interaction [64,65]. The latter may, in turn,
and enzymes with their activity and/or specicity altered. When interfere with the recognition and function of DNA-associated pro-
the mutations are accompanied by changes in the gene informa- teins such as topoisomerases, polymerases, DNA repair systems
tion of a germinal cell, the progeny may inherit such a mutation. and transcription factors, bringing about slowing down or even
When occurring in somatic cells of complex organisms, the muta- inhibition of the transcription and replication processes [66,67].
tions may induce irreversible changes that may end up in tumour Intercalators operate as frameshift mutagens. Even though
growth [82]. Luckily, the major part of the damage can be overcome not all intercalators are genotoxic, basic, cationic or electrophilic
by the reparation systems of the cell DNA, the only unrecoverable functional groups are required for the genotoxic activity [92,93].
damage being, perhaps, the rupture of the two strands of the DNA. Knowledge of the physicochemical behaviour of the reacting sys-
[83]. tem can be of help to elucidate the biological action of drugs capable
Three different ways of drugDNA interaction can be distin- of interacting with DNA. Intercalators are characterized by having
guished. First, drugs may interact with DNA-binding proteins, such an extended planar aromatic structure [94]. Examples of reversible
as polymerases and transcription factors. The second way implies binding agents include potent carcinogens like ethidium bromide,
the RNA binding to the DNA double helices to form RNADNA proavine [95] and benzopyrene [96] (Fig. 3). Positively charged
triple helix hybrids that may interfere with the transcription activ- compounds favour intercalation, because the electrostatic attrac-
ity [84]. The last way, the purpose of this study, consists of the tion between the positive charge and the backbone phosphate
DNA interaction with small molecules [85], referred to as drugs. groups stabilizes the drugDNA interaction [97]. Computational
Most of the anticancer drugs used exert their antitumour effect approaches indicate that the positive charge may cause a lowering
by damaging the replication machinery of DNA either by covalent in the LUMO energy of the ligand, favouring thus the interaction
or non-covalent binding. DNA-binding drugs can be categorized with the HOMO of the DNA bases [34].
according to the type of association with DNA: covalent binding The highly negative electrostatic potential in the DNA grooves
agents, intercalators, groove binders and, most recently classied plays a key role as origin of the groove binding (Fig. 2B) [98]. Small
[86], phosphodiester backbone binders. crescent-shaped molecules have been claimed to bind DNA via

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Fig. 2. Types of non-covalent binding: (A) Distortion caused by intercalation of proavine between two pairs of adjacent bases of the double helix (adapted from [87]). (B)
DNA minor-groove recognition of a tris-benzimidazole drug (adapted from [88]).

NH2

Br-
+
N
H2N H2N N NH2

A B C O

H HN
O N
HN
NH2
NH2 N
HN NH HN
N H
N O
O N
HN N
N N O
H O
O
HN NH
HN NH2
NH2 HN
HN
D E NH2 F

Fig. 3. Intercalating drugs: (A) Ethidium bromide, (B) Proavine and (C) Benzopyrene. Groove binder drugs: (D) Dapi, (E) Netropsin and (F) Dystamicin.

the minor groove. A plethora of hybrid molecules based on dis- the DNA backbone smaller than that caused by intercalation [100].
tamycin or netropsin (Fig. 3) have been synthesized with the aim The combined action of electrostatic, H-bonding and van der Waals
of improving the selectivity and specicity with reduced or even interactions may give rise to complexes more stable than those
null undesired side effects [99]. The two structures display certain brought about only by intercalation [101]. Currently, minor groove
curvature quite adequate to t in with the groove; also, they are binders are in development because they are prone to modulate
endowed with donor or acceptor atoms able to H-bonding with the gene expression, due their high specicity [102].
the atoms of the bases and the DNA backbone phosphate groups. At molecular level, the surroundings of each type of groove
Unlike intercalators, groove binders must have exible structures; differ from the other [103]. Major grooves have multiple interac-
this sort of binding implies lodging of the drug into the grooves of tion sites and display comparatively stronger binding ability with
the double, triple or G-quadruplex helices, causing a distortion of the guest molecules [104,105]. It is 11.6 A width and 8.5 A depth

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G. Barone et al. / Coordination Chemistry Reviews xxx (2013) xxxxxx 5

[106] and offers easy access to bulky molecules [107]. On the other of nucleic acids by metal complexes generally takes place via two
hand, minor grooves have reduced number of binding sites and steps: hydrolysis of the metal complex, leading to formation of
are smaller in size, with 8.2 A depth. However, minor grooves often reactive aqua species, and further nucleophilic attack of purine
have the benet of being free and may afford available room to bind bases, which results in coordination bond between the metal ion
small molecules. Given that most of the antibiotic and anticancer and the DNA nucleobase(s) [58]. Depending on the number and
drugs are small molecules, the minor groove is, in fact, the main location of the leaving groups (e.g. cis or trans geometry) and coor-
binding site [106,108]. The electrostatic effects between cationic dination sites, DNA metallation may provoke alterations in the
species and the negatively charged DNA phosphate backbone are DNA secondary structure, which can include bending or kinking,
ideal nonspecic interactions that might be important to enhance local helix unwinding and also conformational distortions, forma-
the binding of small molecules. By and large, these classical exter- tion of mono- or polyfunctional adducts, and inter- or intra-strand
nal binding interactions generally occur on the outside of the helix, crosslinks [74].
which may be solely electrostatic or else bound to the grooves The second type of interaction occurs by intercalation. Metallo-
(groove binding). intercalators are metal complexes bearing planar aromatic side
The electrostatic interaction named external association groups of the coordinating ligands. As the name suggests, these lig-
involves the action of DNA as a scaffold that enables drugdrug ands, oriented parallel to the base pairs and protruding away from
external interaction [95]. This type of interaction entails changes the metal center, can readily -stack in the DNA duplex. Often, in
in the UV absorption spectra (bathochromic effect), which consti- such complexes the metal ion is part of the planar portion [73].
tutes a notable difference regarding pure electrostatic interaction, The size of the planar fragment together with the shape and type
whose spectral curves remain unshifted. The binding constants of of substituents of the complex are important to discriminate, for
the external association (G = 12,6 kJ mol1 ) are low compared example, between groove binders and intercalators [17].
with intercalation [109]. Both intercalation and external associa- The third type of interaction is electrostatic in nature, and occurs
tion require planar aromatic ligands as reaction partners, thereby between a cationic complex and the anionic phosphate backbone.
these modes of binding can be observed with the same ligand. The Neutralization of this negative charge reduces the repulsive forces
interaction of proavine/DNA in ethanolaqueous media depends between adjacent phosphate groups, thus stabilizing the double
on the ethanol content and ligand (D) to receptor (DNA) ratio [95]. helix. The two former interactions are often selective, whereas elec-
In water, when [DNA] > > [D], it turns out to be [DNA] > 10 [D], and trostatic interactions may occur at any phosphate site along the
the intercalative binding dominates. When the D content increases, phosphate backbone [112].
then [DNA] < [D], and the intercalated entity permits other units
to stack jointly around the polymer backbone. When the ethanol
concentration is raised, then the stack becomes enhanced. 1.3. Techniques used to monitor the metal complex-DNA binding

1.2.3. Interaction of metal ions and metal complexes with nucleic A range of techniques are used to study metal complexDNA
acids interactions. Only X-ray and NMR afford atomic level details of the
Inorganic Chemistry in Medicine can be conveniently split into hostguest binding [113116]. Mass spectrometry, with the intro-
two main categories: rst, ligands acting as drugs with target metal duction of matrix-assisted laser-desorption ionization (MALDI)
ions, whether free or protein-bound; and secondly, metal ion-based and electrospray ionization (ESI) methods, allow direct analysis
drugs and imaging agents in which the central metal ion often is of large and thermally labile biomolecules [117], metal complexes
crucial [61]. Free metal ions can interact with nucleic acids accord- with oligonucleotides and proteins [118]. This technique can be
ing to two distinct binding modes: diffuse binding and site binding, combined with capillary electrophoresis (CE) or high-performance
the two being important for the structure and function of nucleic liquid chromatography (HPLC). HPLC, widely used to separate and
acids. Diffuse binding is a long-range Coulomb interaction, in which determine free metal ions and coordination compounds, shows
positive metal ions retain their hydration layer, building up around high speed and efciency, and can be attached to many sensitive
the nucleic acid in a delocalized manner, the interaction occurring and selective detectors [119121]. CE is based on the separation
through water molecules. In the site binding mode, the metal coor- of species according to charge, size and frictional force under the
dinates to specic ligands on the nucleic acid; the coordination can effect of a high electric eld [122,123]. This efcient and fast tech-
either be direct (inner-sphere) or through a water molecule (outer- nique provides valuable information about cooperativity, afnity
sphere). The nucleophilicity of the coordination site and the steric and selectivity [124,125]. Gel electrophoresis can be used with dif-
effects play a key role [60]. ferent incubation protocols; the assays help to verify intercalative
The nucleic acid bases guanine (G), adenine (A), thymine binding [126,127], topoisomerase inhibition [128] and DNA cleav-
(T) and cytosine (C) have different metal ion afnity. At phys- age [102,129].
iological pH, the preferred binding sites on the nucleobases Footprinting embraces cleavage assays of the backbone of
are: N7 guanine, N1 and/or N7 adenine, N3 cytosine, and O4 nucleic acids by enzymatic or chemical nuclease inhibited by drug
thymine. For nucleotides, the relationship between phosphate binding to specic sequences. Nucleic acid fragments are separated
and base binding depends on the type of metal ion. Based by polyacrylamide CE, disclosing the length and position of the
on the metal-induced variation in thermal denaturation tem- binding sites [130,131]. Specically designed to study the sequence
perature (Tm ) of DNA, Eichhorn and Shin suggested that the selectivity are competition dialysis [132], restriction endonuclease
relative metal afnity to the phosphate backbone of DNA follows protection selection and amplication (REPSA) [133,134], system-
the order Mg2+ > Co2+ > Ni2+ > Mn2+ > Zn2+ > Cd2+ > Cu2+ [110]. How- atic evolution of drugs by exponential enrichment (SELEX) [25] and
ever, a more detailed picture reveals that metal ion binding to uorescent intercalator displacement (FID) [135,136].
base residues is sequence-dependent [111]. As a consequence, one Electron paramagnetic resonance (EPR) is useful to infer the
may envisage designed metal complexes that can bind selectively orientation respect to the helix axis of drugs endowed with a
to chosen DNA sequences. Regarding metal complexes, again the paramagnetic center bound to DNA, as well as conformational
same three main interactions described above occur with oligo- changes of the DNA ber [137]. Raman spectroscopy [138] and
or polynucleotides. The rst type involves covalent interaction Surface-enhanced Raman spectroscopy (SERS) [139] are excellent
between the Lewis acid metal ion and nucleic acid Lewis bases, techniques to assess nucleic acid binding sites and characterize the
such as nucleophilic guanine N7 residues (see Fig. 1A). Metallation DNA conformational changes induced by the drug.

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Surface plasmon resonance (SPR) measures in real time the dealing with the determination of Kb have been implemented on
changes in refractive index as the DNAdrug interaction occurs the basis of the models by Scatchard [157], McGhee and von Hippel
[140], informing about the equilibria and interaction kinetics [141]. [158], Norden and Tjerneld [159], Wolfe et al. [160], Rodger [161],
Atomic force microscopy (AFM) enables direct visualization of Rodger and Norden [162], Kumar and Asuncion [163], Carter et al.
DNAdrug complexes and can be applied under vacuum, in solu- [164]. These procedures are based on the linearization of the law
tion, or in air at room, cryogenic or elevated temperatures [142]. of mass action [165167]. Many analytical methods based on non-
Viscosity and sedimentation hydrodynamic methods are crucial linear multiparametric curve tting algorithms make use of single
to determine the binding mode. Intercalation of the ligand into the wavelength data in cyclic steps to determine Kb and the binding
base-pairs causes local unwinding of the DNA double helix and rise stoichiometry (expressed as the number of DNA bases per bind-
in the contour length, with subsequent increase in the relative vis- ing site) [164,167]. These methods are most often used to analyze
cosity and decrease in the sedimentation coefcient. Such changes spectroscopic or electrochemical titrations of metal complexes in
are absent in groove-binding [143]. the presence of increasing amounts of DNA, and are valid for the
Polarized light spectroscopy enables fast characterization of assumption of non-cooperative and non-specic binding to DNA
DNAdrug complexes. Linear dichroism (LD) is directly related to with one type of discrete binding site. In most cases, the titration
the orientation of the drug with respect to the DNA long axis. Small data are successfully t by equations derived from the Hildebrand-
free drugs in solution are not oriented and give no LD signal; hence, Benesi approach [166168] for low-afnity DNA-binder complexes
the presence of LD proves that the drug is bound to DNA. Intercala- (Kb < 105 M1 , see e.g. [77]), and by equations derived from Carters
tors closely stacked to base-pairs display LD similar to base-pairs, approach [164,167] for complexes with DNA-binding constants
whereas groove binders display opposite LD [144]. Circular dichro- higher than 105 M1 (see e.g. [75,76,169]).
ism (CD) affords additional structural insights into the DNAdrug In the following Sections 2.1 and 2.2 we have collected and
complex. Non-chiral drugs give no signal, so an induced circular compared the Kb values relative to the interaction with DNA
dichroism (ICD) signal in the absorption region of a non-chiral drug of complexes of the three title metal ions with the same lig-
is evidence for DNA binding [145,146]. UVvis absorption and uo- ands, measured under the same experimental conditions. Generally
rescence spectrometry are most used due to their good sensitivity, speaking, the mixed-ligand complex offers variation in geome-
reproducibility, simplicity and versatility. The absorbance and u- try, size, hydrophobicity, and H-bonding ability, the main factors
orescence spectra of drugs become altered upon interaction with to determine the DNA-binding afnity [170]. In this regard, an
nucleic acids, shifting the maxima. Fluorescence enhancement or appropriate comparison of the DNA-binding strength of the three
quenching can be observed upon interaction with nucleic acids metal ions along each row in Tables 1 and 2 can be performed
[147]. because these data have been obtained for exactly the same polynu-
Calorimetric techniques are a powerful tool to obtain ther- cleotide sequence, ionic strength and pH solution conditions [60].
modynamic binding parameters. The thermal denaturation of the In particular, the ionic strength of the medium strongly affects the
DNAdrug complex is evaluated by differential scanning calorime- interaction of the negatively charged double helical polymer and
try (DSC) [148] or UVvis [149] measurements, which provide the metal complexes, often positively charged [171]. The effect of
the thermodynamic properties of the DNA melting. Intercalators ionic strength on the binding constant can be rationalized by the
increase the melting temperature, and thermal stabilization is not Record equation [172], in which the decrease of the binding con-
observed for other binding modes. Isothermal titration calorime- stant, (log K) versus the incremental ionic strength, (log I),
try (ITC) provides the stoichiometry and binding afnity [150,151]. must be linear, and the slope is  m , where m represents the num-
Kinetic experiments enable determination of the reaction mech- ber of phosphodiester residues occupied by one guest molecule and
anism. The data analyses yield the forward and backward kinetic  is the fraction of DNA negative charge counteracted by exter-
constants of each step and the equilibrium constants as well. Non- nal ions. Values m  1.0 are consistent with intercalative binding
covalent interactions are very fast, and must be monitored by [147]. Moreover, the Kb values reported in different rows have been
means of relaxation (T-jump, P-jump) or ow (Stopped ow) meth- obtained by different spectroscopic and electrochemical titration
ods [152,153]. techniques, such as UVvis absorption, uorescence and uores-
Molecular modelling techniques [154] and computational cence quenching by ethidium bromide displacement.
approaches such as molecular dynamics, Monte Carlo simulations Only few recent papers are available on the DNA-binding of
and quantum chemical calculations provide information about nickel(II), copper(II) and zinc(II) complexes, compared with the
binding modes, binding energies, specic sequences, binding afni- analogous studies involving ruthenium or platinum complexes.
ties, stoichiometry and conformational changes of the DNAdrug However, the data reported in Tables 1 and 2 have allowed us to
interaction. Quantum mechanics/molecular mechanics (QM/MM) cover all common coordination geometries and all typical DNA-
methods describe at high QM level a small portion of the whole binding mechanisms. Metal complexes that exhibit interaction
molecular system, which is treated at the lower MM theory level. with DNA have been studied with the aim of developing probes
These methods provide structural and energetic results concern- for nucleic acid structures and chemotherapy agents [173]. By
ing the high level layer more reliably than those obtained by MM changing the ligand environment, it is possible to study the DNA
methods. For example, the QM/MM methodology, with density binding and cleavage ability of metal complexes. Such studies are
functional theory (DFT) used to describe the higher-level QM layer, also important to evaluate the mechanism of metal ion toxicity
has allowed to successfully reproduce the coordination geom- [174,175]. The results reviewed have been classied in terms of
etry and spectroscopic properties of metalloprotein active sites Schiff base ligands (Table 1, Section 2.1) and other ligands (Table 2,
[155,156]. Section 2.2). In the reviewed papers, the associated error is roughly
one tenth of the Kb value, the observed difference between the Kb
values being a signicant turning point.
2. Nickel(II), copper(II) and zinc(II) DNA-binding complexes
2.1. Schiff base ligands
The intrinsic binding constant, Kb , provides a reliable indication
on how guest and host molecules bind. In particular, Kb constants The interaction of DNA with nickel(II), copper(II) and zinc(II)
constitute a valuable tool to quantify the interaction afnity complexes involving Schiff-base ligands has been extensively
between small molecules and DNA [60]. Available methods of investigated. Due to their novel electronic and/or magnetic

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properties with fascinating structural features and the easy mod- 103 M1 < Kb < 108 M1 . Moreover, with the only exception of
ulation of their DNA binding and cleaving ability, Schiff-base L15 [178], the complexes prove to be more efcient DNA-
metal complexes of multidentate aromatic ligands currently binders and biologically more active than their coordinating free
attract renewed interest in medicinal chemistry and in the ligands. Ligands L1L4 [56,57,179,180] give rise to metal com-
development of new therapeutic agents [96,176,177]. The bind- plexes with decreasing afnity with DNA in the order Ni > Cu > Zn
ing constants of the metal complexes of Table 1, in each row and the corresponding binding constants lie in the range
essentially sharing same coordination geometry, lie in the range 103 M1 < Kb < 106 M1 .

Table 1
Intrinsic DNA-binding constants, Kb , for nickel(II), copper(II) and zinc(II) complexes of Schiff base ligands, as indicated.

Label Ligand Ni Cu Zn Ref.

L1 4.3 106 1.3 106 7.3 104 [56,57]

L2 4.5 106 (S); 1.1 106 (S); 6.5 105 (S); [179]
5.1 105 (R) 2.3 105 (R) 2.0 105 (R)

L3 1.6 103 1.5 103 1.3 103 [180]

L4 2.1 104 1.4 104 1.1 104 [180]

L5 5.7 104 4.5 104 [181]

L6 1.7 104 (R = H); 2.7 104 (R = H); 1.0 104 (R = H); [182]
2.3 104 (R = OMe) 3.7 104 (R = OMe) 1.6 104 (R = OMe)

L7 1.07 105 2.34 105 1.03 105 [183]

L8 1.87 103 2.02 104 1.16 104 [184]

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Table 1 (Continued)

Label Ligand Ni Cu Zn Ref.

L9 3.16 105 9.37 105 4.59 105 [185]

L10 2.2 104 4.3 104 1.3 104 [186]

L11 1.9 104 1.03 105 1.9 104 [186]

O O
H H H
N N H
N N N N
L12 H N NH H 9.8 103 1.25 104 7.3 103 [187]
S S

L13 8.72 107 3.27 108 [190]

L14 3.55 104 2.33 104 [192]

L15 0.56 104 0.91 104 [178]

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Table 1 (Continued)

Label Ligand Ni Cu Zn Ref.

L16 2.3 105 4.7 104 1.5 105 [193]

Table 2
Intrinsic DNA-binding constants, Kb , for nickel(II), copper(II) and zinc(II) complexes, as indicated.

Label Complex Ni Cu Zn Ref.

ML1 2.7 104 1.0 104 2.2 104 [194]

ML2 9.1 104 7.5 104 8.1 104 [194]

ML3 4.79 104 1.84 104 2.38 104 [195]

ML4 9.52 104 2.50 104 2.93 104 [195]

ML5 1.55 104 0.98 104 [43]

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Table 2 (Continued)

Label Complex Ni Cu Zn Ref.

ML6 5.72 104 2.06 104 [43]

ML7 6.10 105 7.37 105 1.07 105 [196]

ML8 4.56 104 6.47 103 6.70 103 [197]

ML9 7.68 103 7.08 103 3.39 104 [198]

ML10 0.98 104 3.4 104 [201]

ML11 3.80 104 3.07 104 [201]

ML12 7.50 104 [201]

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Table 2 (Continued)

Label Complex Ni Cu Zn Ref.

ML13 6.7 106 4.7 105 [76]

ML14 3.27 105 1.87 105 [204]

The L1, L3 and L4 complexes Exhibit 1:1 metal ion-to-ligand the two metal ions in the same plane of the ligand, and two api-
stoichiometry, whereas L2 complexes show 1:2 stoichiometry and cal water molecules per metal ion lling the six coordination sites.
the copper(II) complex of L3 is binuclear. Concerning the structural Ligands L10 and L11 act as tri- or tetradentate chelates, with N2 O2
features, the L1 and L2 ligands possess N2 O2 donor groups and can or NO2 (L10) and NO3 (L11) donor atoms, respectively. The DNA
form complexes with a square planar geometry that presumably binding of all complexes was analyzed by electronic absorption
undergoes tetrahedral distortion from Ni to Cu to Zn. Complexes of spectroscopy, viscosity measurements and cyclic voltammetry and,
the tridentate ligands L3 and L4, which present NO2 and N2 O donor in the case of L6 complexes, rationalized with the help of molecu-
groups, respectively, are octahedral with two water molecules and lar modelling. The results obtained have been interpreted in terms
one chloride anion as additional coligands. Nickel(II) and copper(II) of DNA-intercalation, except for L6 complexes; for the latter, the
L5 complexes [181] fall in the same category, the tetradentate N2 O2 authors assign groove binders, although in our opinion the trends
ligand giving rise to a square planar copper(II) complex and an octa- of the spectroscopic and viscometry titrations do not allow one to
hedral nickel(II) complex, the latter bearing two additional water exclude partial DNA-intercalation.
molecules as apical ligands. The trend of the Kb values, in the order Cu > Ni > Zn, induce to
The results of spectrophotometric and viscometry titrations hypothesize coordination of a N or O donor atom of the nitro-
assign an efcient DNA-binding ability to each compound and sug- gen bases or of the sugar-phosphate backbone of DNA, in addition
gest the occurrence of intercalation. The observed trend of the Kb to the non-covalent interaction. In fact, such a trend follows the
values suggests that the increased planarity of the L1L4 metal IrwingWilliams series [188,189], which is typical of coordination
complexes, from Zn to Cu to Ni, appears to enhance the DNA inter- complexes of the three metal ions with the same ligand and the
calation ability. Small differences in the Kb values were observed same coordination geometry. Lastly, all the compounds show inter-
for complexes with L3L4, for which the intercalating moiety is esting antibacterial and/or antioxidant activity.
presumably represented by the naphthalene group. As such, the The nickel(II) and copper(II) complexes with L13 [190] fulll
nature of the metal ion affects to a smaller extent the DNA binding the same Kb sequence and show the strongest DNA-binding afn-
of the overall complex. Interestingly, the binding constants of the ity (Kb > 107 M1 ) among those reported in Table 1. The structure
mono-cationic complexes of L4 are an order of magnitude higher of the binuclear complexes allows supramolecular rigid structures,
than those of the neutral ones of L3. The positive charge of the com- similar to those of iron and ruthenium [191], with the metal ion
plexes of L3 enhances the interaction with the negatively charged hexacoordinated in a distorted octahedral geometry. This similar-
sugar-phosphate backbone of DNA. Except for the metal complexes ity, along with the overall charge 4+, permits one to hypothesize
with the L1 ligand, the biological activity of which so far has not strong electrostatic major groove binding for the two complexes.
been tested, all the above complexes show promising antibacterial As a matter of fact, the compounds developed by Hannon et al. [191]
activity. also show a binding constant in excess of 107 M1 and induce DNA
Ligands L6L12 [182187] give rise to nickel(II), copper(II) and bending and intramolecular coiling. These results make it difcult
zinc(II) complexes in which the DNA-binding strength follows to justify one order of magnitude difference in the Kb values of the
the order Cu > Ni > Zn and the binding constants lie in the range copper(II) complex compared with the nickel(II) complex.
103 M1 < Kb < 105 M1 . L6 and L9 complexes show square planar The sequence followed by the copper(II) and zinc(II) com-
coordination geometry, with the tetradentate chelating ligand L6 plexes of L14 [192] and L15 [178] ligands (Cu > Zn) falls within the
coordinating through the typical N2 O2 donor groups, whereas L9 two previous categories. The metal complexes of L14 show a 1:1
presents N4 chelation. L6 yields neutral metal complexes after ligand:metal stoichiometry, whereas the coordination geometry
deprotonation of the two coordinating OH groups. All nickel(II), is tetrahedral for zinc(II) complex and square pyramidal for cop-
copper(II) and zinc(II) complexes of ligands L7, L8, L10, L11 and per(II) complex, with an apical coordinating water molecule. The
L12 are octahedral. The crystallographic data gathered show that complexes interact with DNA by groove binding and partial interca-
the structure of complexes of the tridentate ligand L7 is a distorted lation. The copper(II) complex exhibits a remarkable DNA cleavage
octahedron, with two water molecules and one nitrate lling the six activity. The metal complexes of L15 show a 1:2 ligand:metal stoi-
coordination sites. Neutral and binuclear metal complexes of the chiometry, while the coordination geometry is square planar, with
hexadentate ligands L8 and L12 show octahedral geometry, with an apical coordinating water molecule. Both copper(II) and zinc(II)
the planar ligand coordinating each of the two metal ions by three complexes of L15 signicantly bind to DNA, presumably by inter-
donor atoms, N2 O or N2 S, respectively, with a chloride bridging calation, although to a lesser extent than the free ligand.

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Among those reported in Table 1, only the L16 [193] metal com- For nickel(II), copper(II) and zinc(II) trigonal pentacoordinated
plexes bind to DNA in the decreasing afnity sequence Ni > Zn > Cu. complexes, ML8 [197], the metal coordination of the tetradentate
A similar trend has been observed for non-Schiff base ligands (see N2 O2 ligand, is completed by a chloride anion. The coordination
below). The proposed coordination number is 4 for Ni, with ligand geometry is intermediate between square pyramidal and trigonal
L16, chelating through the N and S atoms, and 5 for Cu and Zn, with bipyramidal. The metal complexes cause oxidative cleavage of plas-
tridentate L16, through N2 S donor atoms, and two chloride anions mid DNA at very low concentration and without addition of any
as coligands in both cases. The proposed DNA-binding mechanisms exogenous agent. The binding constants for these compounds lie in
are groove binding and intercalation. the order Ni > Zn > Cu and are one order of magnitude smaller than
that of the free ligand.
Nickel(II), copper(II) and zinc(II) complexes ML9 [198] are
2.2. Other ligands DNA-intercalators. They are the only known complexes, in recent
literature, for which the Kb values follow the afnity trend
The DNA-binding of nickel(II), copper(II) and zinc(II) com- Zn > Ni > Cu. The same trend was found in the interaction of met-
plexes of chelating homo- or heteroleptic heterocyclic ligands allopyrazoliumylporphyrins with calf thymus DNA [199]. In the
has been investigated, with Kb values within the range paper mentioned, this peculiar trend was put down to a differ-
103 M1 < Kb < 107 M1 . Such DNA-binding often is accompanied by ent interaction mode and preferential DNA-sequence afnity of the
in vitro cytotoxic activity against human carcinoma cells. Most of non-intercalating zinc(II) complex compared with both nickel(II)
the structures of the metal complexes reported in Table 2 have and copper(II) intercalating complexes. Furthermore, the metal ion
been determined by X-ray crystallography and are characterized center of the metalloporphyrin is presumably coordinated by the
by N,N-donor polypyridyl ligands such as 2,2 -bipyridine or 1,10- CO group and/or the ring-nitrogen of the DNA base pairs [199]. Fol-
phenanthroline. In general, the extension of the planar area of the lowing the DNA-binding afnity trend, the zinc(II) complex ML9
ligand is accompanied by an increase in the DNA-binding constant, exhibited the highest antitumour activity. A remarkable change of
with subsequent enhanced DNA-intercalation ability. the metal complex structure occurs after the DNA-binding, with
More in detail, the heteroleptic nickel(II), copper(II) and zinc(II) possible exchange of the water ligand(s), which should be more
complexes of tris(3-phenylpyrazolyl)borate and N,N-donor het- advantageous for zinc(II) compared with both nickel(II) and cop-
erocyclic bases, ML1 and ML2 [194] assume a pentacoordinate per(II) complexes. In this context, a similar trend was found also
square-pyramidal geometry, in which two N atoms of the poly- for the covalent binding to nucleobases of nickel(II), copper(II) and
heterocyclic base and two N atoms of the borate ligand occupy the zinc(II) complexes of tetradentate macrocyclic tetraamine deriva-
basal plane and one N of the latter ligand is bound at the axial site. tives [200]. For these compounds, DFT calculations have shown that
The three complexes are DNA minor groove binders, with bind- the stability of the square planar coordination of the three metal
ing constants of the order 104 M1 . The binding constants decrease ions decreased in the order Ni > Cu > Zn. However, coordination of
in the order Ni > Zn > Cu, an effect probably due to the pentaco- the metal ion by the donor nitrogen base, produced a pentacoordi-
ordinated geometry of these complexes, which is more suitable nate square planar geometry and inversion of the stability order to
for zinc(II) and nickel(II) relative to copper(II). DNA-binding stud- Zn > Cu > Ni [72]. This result shows that essential atomistic informa-
ies were carried out using data from viscosity measurements and tion, concerning the metal complex-DNA binding, could be found
various spectral techniques. The complexes exhibit photoinduced with the aid of computational chemistry.
DNA-cleavage activity [194]. Copper(II) and zinc(II) ternary complexes of N,N-donor che-
ML3 and ML4 [195] nickel(II), copper(II) and zinc(II) complexes lating polyheterocyclic ligands ML10, ML11 and ML12 [201] are
as well as ML5 and ML6 [43] copper(II) and zinc(II) complexes, dicationic and showed octahedral coordination geometry. Their
are all DNA-intercalators. The Kb values of ML3 and ML4 also interaction with calf thymus DNA revealed DNA-binding afnity of
fulll the sequence Ni > Zn > Cu, whereas those of ML5 and ML6 the order of 104 M1 , indicating groove binding with partial inser-
follow the afnity trend Cu > Zn. These complexes show distorted tion. The increase of the binding constant, from ML10 to ML11 to
octahedral geometry. A bidentate Schiff-base and two bidentate ML12, has been interpreted considering that a progressive exten-
2,2 -bipyridine or 1,10-phenanthroline ligands, respectively, coor- sion of the central planar core allows deeper intercalation of the
dinate the Ni, Cu and Zn metal ions in ML3 and ML4. A tridentate complexes. These induce oxidative cleavage of DNA, also in the
Schiff-base, a chloride and a bidentate 2,2 -bipyridine or 1,10- absence of H2 O2 .
phenanthroline ligand, respectively, coordinate the Cu and Zn ions The values of the DNA-binding constants of copper(II) and
in ML5 and ML6. In this regard, the higher afnity of the com- zinc(II) ML13 complexes [76] follow the order Cu > Zn. The macro-
plexes containing phenanthroline compared with those bearing the cyclic ligand is N4 tetradentate and the structure of both complexes
bipyridine ring system, has been attributed to the more extended is square pyramidal, with bromine or perchlorate as coordinated
size, and the subsequent improved intercalation ability of the apical ligand [202,203]. The distribution diagrams have shown
former ligand. The Kb values deduced, lower than those observed that, at neutral pH, both copper(II) and zinc(II) complexes are
for typical classical intercalators, have been attributed to the steric present as stable dicationic species, after dissociation of the apical
hindrance of the Schiff-base coligand, which hampers the non- ligand or displacement by H2 O [202,203]. The proposed interac-
covalent interaction with DNA. tion mechanism is DNA-intercalation, without excluding possible
Nickel(II), copper(II) and zinc(II) complexes of ML7 [196] have coordination of the metal ion by heterocyclic donor atoms of the
a similar molecular structure, the ligand behaving as N2 bidentate nitrogen bases [76]. Such compounds, delivered through the cell
and assuming coplanar conformation after coordination with the membrane by a lipidic carrier, showed in vitro cytotoxic activity
metal ions. Two nitrate anions coordinate as bidentate (for Ni and against human carcinoma cells.
Zn) and as monodentate (for Cu) ancillary ligands. The observed Copper(II) and zinc(II) ML14 [204] show distorted trigonal
trend in the DNA-binding constants, Cu > Ni > Zn, suggests also in bipyramidal coordination geometry. Experimental and computa-
this case that, in addition to DNA-intercalation, metal coordina- tional investigations, the latter by molecular docking approaches,
tion by heterocyclic donor atoms of nitrogen bases may also occur. suggest DNA-intercalation through the minor groove, character-
Interestingly, also the antitumour activity of these compounds ful- ized by high afnity and selectivity. The higher Kb value with
ls the sequence Cu > Ni > Zn, in fairly good agreement with the copper(II), compared with the zinc(II) complex, has been attributed
DNA-binding afnity trend. to occurrence of N7 coordination of the copper ion, which is

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stronger than the N3 coordination occurring in the zinc complex. 3.2. Covalent and/or non-covalent interactions?
The Kb trend, Cu > Zn, is parallelled by the in vitro antimicrobial
activity [204]. Taking into account the common trend of metal complexes to
increase their coordination number from 4 to 6, for square-planar
complexes it is not viable to exclude further more or less labile
3. Rationalization of the literature results coordination of the apical site to the metal ion by the O and/or N
atoms of the nitrogen bases. The DNA-binding strength, in order
3.1. Geometry and electronic structure of the metal complexes of decreasing Kb values, Cu > Ni > Zn, supports such hypothesis,
considering that DNA-metal complex supramolecular complexes
An analysis of the DNA-binding constants listed in Tables 1 and 2 should form a coordination structure similar for the three metal
reveals that the interaction of the three metal complexes can be ions and thus the Irwing-Williams series is strictly followed. Such
split into the following three categories, for which the DNA afnity a rule should help the reader to argue the presence of covalent
strength decreases in the order: bonds involving the metal ion, in addition to the non-covalent
interactions, on the basis of ngerprint criteria following the trend
of the changes in shape that occur along the spectrophotometric
(1) Ni > Cu > Zn; and viscometry titrations. Hence, the original tetracoordination
(2) Cu > Ni > Zn; structure should change to penta- or hexa-coordination to form-
(3) Ni > Zn > Cu. ing the supramolecular metal-ligand-DNA complex. In this case,
the DNA macromolecule should behave as an additional coordinat-
ing ligand, through the donor O and/or N atoms of the nitrogen
Only in one case was the afnity of the three metal complexes bases or of the sugar-phosphate backbone. Nevertheless, metal
towards DNA in the order Zn > Ni > Cu. To nd out the crucial fac- coordination by DNA donor atoms has been detected also in other
tors that determine the DNA-binding strength, the literature data instances, remarkably when the DNA afnity trend was Zn > Ni > Cu.
were surveyed considering the coordination chemistry of the com- This feature shows that the results of DNA-binding studies can be
pounds listed in Tables 1 and 2, which are indeed tetra-, penta- and rationalized on the basis of the coordination chemistry properties
hexacoordinate nickel(II), copper(II) and zinc(II) complexes. The of the metal complex, determining either sequence selectivity or
analysis reveals that tetracoordinate complexes normally behave nonspecic afnity. DNA binding details can be assessed by com-
as DNA-intercalators and pentacoordinate compounds are DNA- parison with available literature data on similar compounds and by
groove binders, whereas hexacoordinate complexes can be groove the support of computational chemistry.
binders, intercalators or both.
Tetracoordinate complexes, the most common among Schiff-
4. Conclusions
base derivatives, assume square-planar or distorted tetrahedral
geometry, in agreement with the coordination chemistry proper-
In the present survey the intrinsic DNA-binding constants of
ties of these compounds described in standard textbooks [188,189].
nickel(II), copper(II) and zinc(II) complexes have been collected,
For example, tetracoordinate nickel(II) complexes of strong eld
with an effort to rationalize the observed afnity trends in terms of
ligands tend to assume stable square-planar geometry. In addition,
their structural and electronic properties. The reviewed data have
the square-planar geometry of nickel(II), copper(II) and zinc(II)
been discussed on the basis of well-known DNA-binding modes,
complexes is forced by cyclic porphyrin-like tetradentate ligands,
which can be deduced by qualitative and quantitative interpreta-
with O or N donor atoms. However, in the presence of heterocyclic
tion of spectroscopic and hydrodynamic titrations performed in
ligands with N donor atoms, going from Ni to Cu to Zn, it is expected
buffered aqueous solutions. The suggestion to sort out the DNA-
that the structures of these complexes undergo monotonic distor-
binding afnity by both the order of magnitude and the trend of
tion from square-planar to tetrahedral geometry.
Kb values, going from Ni to Cu to Zn, could support the analy-
Hexacoordinate complexes in Tables 1 and 2 assume almost
sis of further DNA-binding studies of the three metal complexes,
exclusively octahedral coordination geometry. Moreover, as seen
which are expected to increase exponentially in the near future.
for most of the DNA-binder transition metal complexes, they
In perspective, the above considerations reinforce the role that
behave as groove binders, intercalators or both, depending on the
Computational Chemistry may play as a valuable diagnostic tool
size of the planar moiety of the coordinated ligands [17]. In this
to interpret spectroscopic or hydrodynamic measurements and to
regard, d8 and d9 complexes, like those of nickel(II) and copper(II),
unveil the ensuing metal complex-DNA binding. In this way, it
show preference for octahedral rather than for tetrahedral geome-
should be possible to reliably account for both covalent and non-
try [188]. This feature indicates that, in the presence of additional
covalent binding between a metal complex and a DNA model.
coordinating ligands, as for example the donor exo- or heterocyclic
N and O atoms of DNA, an increase in the coordination number
Acknowledgements
can be expected for tetracoordinated copper(II) and nickel(II) com-
plexes. For the same reason, such a condition is not always strictly
The nancial support by Ministerio de Educacin y Ciencia,
fullled by tetracoordinate zinc(II) complexes, characterized by d10
Project CTQ2009-13051/BQU, supported by FEDER, Junta de Castilla
electron conguration and the absence of Ligand Field Stabiliza-
y Len, Project BU-299A12-1 and Project Obra Social la Caixa, are
tion Energy [188,189], because their change in geometry will not
gratefully acknowledged.
straightforwardly determine structural stabilization.
Pentacoordinate complexes show an intermediate behaviour
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