Chapter 1
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1
INTRODUCTION
1.1 General overview on DNA
Working in the 19th century, biochemists initially isolated DNA and RNA
(mixed together) from cell nuclei. They were relatively quick to appreciate the
polymeric nature of their "nucleic acid" isolates, but realized only later that
nucleotides were of two types: one containing ribose and the other
deoxyribose. It was subsequent discovery that led to the identification and
naming of DNA as a substance distinct from RNA.
In 1929, Phoebus Levene had identified the components (the four bases, the
sugar and the phosphate chain) and he showed that the components of DNA
were linked in the order phosphate-sugar-base.
He called each of these units as a nucleotide and
suggested the DNA molecule consisted of a
string
of
nucleotide
units
linked
together
through the phosphate groups, which are the
'backbone' of the molecule. However, Levene
thought the chain was short and that the bases
repeated in the same fixed order. Max Delbrück,
Nikolai V. Timofeeff-Ressovsky, and Karl G.
Zimmer published results in 1935 suggesting
that chromosomes are very large molecules the
structure of which can be changed by treatment
Francis Crick's first sketch of
the deoxyribonucleic acid
double-helix pattern
with X-rays, and that by so changing their structure. It was possible to
change the heritable characteristics governed by those chromosomes. In
1937, William Astbury produced the first X-ray diffraction patterns from
DNA. He was not able to propose the correct structure but the patterns
showed that DNA had a regular structure and therefore it might be possible
to deduce what this structure was.
In 1948 Pauling discovered that many proteins included helical shapes.
Pauling had deduced this structure from X-ray patterns and from attempts
to physically model the structures (Pauling was also later to suggest an
incorrect three chain helical structure based on Astbury's data). Even in the
initial diffraction data from DNA by Maurice Wilkins, it was evident that the
structure involved helices. But this insight was only a beginning. There
remained the questions of how many strands came together, whether this
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number was the same for every helix, whether the bases pointed toward the
helical axis or away, and ultimately what were the explicit angles and
coordinates of all the bonds and atoms. Such questions motivated the
modeling efforts of Watson and Crick. In their modeling, Watson and Crick
restricted themselves to what they saw as chemically and biologically
reasonable.
Chargaff had observed that the proportions of the four nucleotides vary
between one DNA sample and the next, but that for particular pairs of
nucleotides i.e. adenine and thymine, guanine and cytosine. The two
nucleotides are always present in equal proportions. Nucleotides are the
building blocks of all nucleic acids. Nucleotides have a distinctive structure
composed of three components covalently bound together:
•
•
•
a nitrogen-containing "base"either a pyrimidine (one ring) or
purine (two rings)
a 5-carbon sugar ribose or deoxyribose
a phosphate group
DNA and RNA are synthesized in cells by DNA polymerases and RNA
polymerases. Short fragments of nucleic acids also are commonly produced
without enzymes by oligonucleotide synthesizers. In all cases, the process
involves forming phosphodiester bonds between the 3' carbon of one
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nucleotide and the 5' carbon of another nucleotide. This leads to formation
of the so-called "sugar-phosphate backbone".
A key feature of all nucleic acids is that they have two distinctive ends: the 5'
(5-prime) and 3' (3-prime) ends. This terminology refers to the 5' and 3'
carbons on the sugar. For both DNA and RNA shown above, the 5' end bears
a phosphate, and the 3' end a hydroxyl group.
Most DNA exists in the famous form of a double helix, in which two linear
strands of DNA are wound around one another. The major force promoting
formation of this helix is complementary base pairing: A's form hydrogen
bonds with T's (or U's in RNA), and G's form hydrogen bonds with C's.
DNA is composed of a series of polymerized nucleotides, joined by
phosphodiester bonds between the 5' and 3' carbons of deoxyribose units. A
double helix is formed between the two strands, running in opposite
directions [1-2]. The nucleotide bases form hydrogen bonds to maintain the
structure, with two bonds between adenine and thymine bases and three
between cytosine and guanine residues. These bases are in the center of the
double helix, with the deoxyribose and phosphate groups on the outside.
The most common form of the DNA double helix is referred to as B-DNA. The
B-DNA helix contains two grooves; the major groove and the minor groove.
The major groove is wider and deeper. There is a greater opportunity for
interactions in the major groove due to its larger size. In addition, there is a
potential for hydrogen bonding with the base pairs in these grooves, as there
is access to both sides of DNA. A-DNA is a helical form that is generated
when the duplex is dehydrated. This helix is wider and shorter than B-DNA,
and has a narrower major groove and almost no minor groove. A third DNA
species is the Z-DNA, which consists of a left handed helix (A- and B-DNA
are right handed). Z-DNA has only a single groove, and this form is present
in oligonucleotides with alternating pyrimidine and purine bases. Most
physiological DNA is present in the B- form.
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1.2 Modes of DNA Interactions
The drugs (DNA binding species/‘ligands’) can interact with DNA, primarily,
in the following ways:
•
Groove binding,
•
Intercalation,
•
Electrostatic binding,
•
Covalent and coordinate
covalent binding.
1. Groove binding
Groove binding drugs, reviewed in detail
by Zimmerman and Wahnert (1986),
generally interact with the DNA minor
groove. Minor groove binding drugs are
usually
crescent
shaped,
which
complements the shape of the groove
and facilitates binding by promoting van
der
Waals
interactions.
Additionally,
these drugs can form hydrogen bonds to
bases, typically to N3 of adenine and O2
of thymine. Most minor groove binding
drugs bind to A/T rich sequences. This
preference in addition to the designed
propensity
for
the
electronegative
pockets of AT sequences is probably due
to better van der Waals contacts between the ligand and groove walls in this
region, since A/T regions are narrower than G/C groove regions and also
because of the steric hindrance in the latter, presented by the C2 amino
group of the guanine base. However, a few synthetic polyamides like
lexitropsins and imidazole-pyrrole polyamides have been designed which
have specificity for G-C and C-G regions in the grooves. Some of the most
commonly studied minor groove-binding compounds, such as distamycin A,
netropsin, and the bisbenzimidazole dyes (Hoechst dyes) [e.g., 2'-(4ethoxyphenyl)-5-(4-methyl-1-piperazinyl)-2,5'-bi-lH-benzimidazoletrihydro
chloridetrihydrate (Hoechst 33342) and 2'-(4-hydroxyphenyl)-5-(4-methyl-1-
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piperizinyl)-2,5'-bi-lH-benzimidazole
pentahydrate
netropsin,
(Hoechst
berenil
and
trihydrochloride
33258)],
DAPI
5
[Ru(phen)3]2+,
(4',6-diamidino-2-
phenylindole), etc. are known to bind to the minor
groove of DNA with A+T specificity and to cause
widening of the minor grooves.
Some major groove binders can be summarized as
enantiomeric complexes Λ- and Δ-[Ru(bpy)2(pqx)](PF6)2
[pqx = 2-(2’-pyridyl)quinoxaline] [3].
Minor groove binding
2. Intercalation
It was first proposed by Lerman (1961), these contain planar heterocyclic
groups which stack between adjacent DNA base pairs. The complex, among
other factors, is thought to be stabilized by π-π stacking interactions
between the drug and DNA bases. Intercalators introduce strong structural
perturbations in DNA. If the ligand has an extended
aromatic portion, it can position itself between the
base pairs, in a sandwich like complex. This
phenomenon, called intercalation [4-6] was first
described by Lerman to explain the binding of
aminoacridines to DNA [7]. Intercalation increases
the separation of adjacent base pairs and the
resulting
helix
adjustments
in
distortions
the
sugar
are
compensated by
phosphate
backbone,
Intercaltion
generally by an unwinding of the duplex. Ethidium bromide (EtBr) is the
classical example of a DNA intercalator [5-6]. Ciprofloxacin one of the ligands
used in this thesis is also an intercalating agent as reported by Vilfan et al.
(2003) [8].
3. Electrostatic binding
Electrostatic or external binding occurs when cations or cationic molecules
are attracted to the anionic surface of DNA. Ions and charged metal
complexes such as Na+ associate electrostatically with DNA by forming ionic
or hydrogen bonds along the outside of the DNA double helix. Although
divalent cations would normally be expected to stabilize the DNA double
helix
by
screening
electrostatic
repulsions
[9],
instead
those
high
concentrations of transition metal cations destabilized the double helix,
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causing base unpairing, unstacking and backbone disorder at lower
temperatures than observed with monovalent cations, or divalent alkaline
earths.
Several
workers
have
observed
that
at
low
concentrations
magnesium stabilizes the double helix [10-11], but at higher concentrations
it lowers the helix coilmelting temperature. This effect is even greater for
transition metal ions, polyamines that bind to the heterocyclic atoms of the
DNA bases as well as to the phosphates [12-13].
An interesting example of the electrostatic DNA binding is Co[NH3]63+ [14].
Proposed two-stage mechanism to explain: the cobalt hexammine binding to DNA in the 1st
stage and DNA condensation in the second stage. Bound counter ions are delocalized or
bound by short-lived hydrogen bonds.
4. Covalent and coordinate covalent binding
It occurs via replacement of the labile ligands by
covalent binding to nitrogen base of the DNA. Such
type of binding is observed for the case of complex
where easily replaceable ligands like halides, aquo
etc.
are
present.
irreversible
and
Covalent
binding
invariably
leads
in
to
DNA
is
complete
inhibition of DNA processes and subsequently cell
death. Cis-platin (cis-diamminedichloroplatinum) and
analogous are famous covalent binder used as
anticancer drugs, and makes an intra/interstrand
cross-link via the chloro groups with the nitrogens on
Covalent adduct
the DNA bases [15-17].
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1.3 Various techniques to probe the DNA binding
Study of the chemical reactions of metal complexes with DNA requires
careful choice of the type of DNA used and method of analysis. The biological
significance of the interaction between metal ions and nucleic acids has
become a rather well-established fact. One may mention the observed
necessity for the presence of metal ions in many natural processes where
nucleic acids play the dominant role. The effect of platinum-based
chemotherapeutic drugs probably originates from their attack on DNA.
Another aspect of metals in biological systems is the increased flux of metals
in the environment during the last decades. An assessment of the toxic effect
of an unnatural metal ion concentration must include information on the
process on which the metal can participate.
Techniques used in DNA structure determination, DNA-Metal ion/Metal
complex interactions are listed below,
1. Direct structure determination methods
2. Indirect methods
1.3.1 Direct methods
The most important method, at least from a historical point of view, has
been the analysis of DNA structure by X-ray diffraction. This is the tool
which was used to discover the basic double-helical form of DNA in 1953.
Since 1980, many important structures of DNA oligomers, and of their
complexes with antibiotics or proteins, have been analyzed in single crystals
by X-ray diffraction methods. Molecule of DNA lay onto a ‘grid’, and applies a
heavy-metal stain such as uranium or platinum in order to help visualize
the DNA in the electron beam. Then one surrounds the grid by a vacuum
and shoots electrons through the sample.
Electron microscopy experiments are easy to perform, but the pictures are
lacking in atomic detail. Furthermore, DNA can easily be distorted from its
natural shape in the course of preparation for electron microscopy, since it
must be removed from the fluid which normally surrounds it and be placed
in a vacuum. The images produced by electron microscopy generally show
the molecule of interest in just two dimensions, unless special care is taken
to tilt the grid and shoot successive pictures from different perspectives [1820].
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Both X-ray structure analysis and electron microscopy are direct techniques
for determining the structure of DNA. However, not all scientists practice
these two methods, because: (a) the necessary equipment is expensive; (b) a
scientist must be highly trained in order to carry out such analyses; and (c)
it is often difficult to prepare a suitable crystal, or indeed a sample for
electron microscopy, of a biologically interesting substance.
For those reasons, many scientists today use a variety of indirect methods
for finding out about the structure of DNA. Most of the indirect methods are
less reliable than the direct methods, but they are generally cheaper and
simpler to perform. Several different kinds of indirect method can be applied
to probe the DNA. This covers the spectroscopic methods and physical
methods.
1.3.2 Indirect methods
Indirect methods can be divided in to two distinct types.
i.
i.
Spectroscopic methods
ii.
Physical methods
Spectroscopic methods
1. NMR spectroscopy
Nuclear magnetic resonance (NMR) spectroscopy is the method of choice for
investigation of the conformation of short (up to/about 25 base pairs)
nucleic acid fragments in solution. Compared to other spectroscopic
techniques, NMR is rather insensitive and requires mili molar sample
concentrations. However, the structural information that may be gained
from NMR spectrum is much more detailed than that available from any
other solution-phase technique and is complementary to that available from
X-ray diffraction studies on solid samples. Indeed, interpretation of NMR
data often requires an assumption of a structure, which may be based on an
X-ray diffraction structure of the specific or a related molecule. Solutionstate NMR data can also reveal flexibility and dynamic behavior.
The effects of adding paramagnetic metal ions to an aqueous solution of DNA
fragments may be monitored by observing the decrease in spin-lattice (T1)
and spin relaxation times (T2) (related to line-broadening) for protons close to
the metal centers. Paramagnetic metal ions may be classified according to
their electronic correlation times, i.e. as relaxation probes producing broad
lines or as paramagnetic shift probes producing narrow lines.
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Paramagnetic relaxation arises in NMR spectroscopy when an unpaired
electron spin interacts with a nuclear spin. The large magnaetogyric ratio of
the electron compared to that of the proton makes the dipolar coupling to
the electron spin a very effective means of relaxation for the nuclear spin.
Scalar interactions between the electron and nuclear spins have similar
effects. In the simplest possible case, a ligand molecule exchanges between
paramagnetic environment (e.g. bound to Mn(II), S=5/2) and a ‘free’ state,
when the ligand is present in solution in vast excess to the paramagnetic
center. The effect of paramagnetic metal ions located at specific binding sites
on DNA is observed as differential line-broadening of proton signals close to
the binding site. Often, in 1D spectra of oligonucleotide molecules containing
ten base pairs or more, key proton resonances may be severely overlapped,
preventing an accurate assessment of the influence of the added metal ions.
In these cases, 2D NOESY experiments may be used to obtain sufficient
resolution. For diamagnetic metal ions (no unpaired spin) the formation of a
chemical bond is usually found to cause changes in the chemical shifts of
proton resonances of hydrogen atoms in the proximity of the metal binding
site. This could be explained by a down-field chemical shift change, induced
by metal binding, being cancelled by an up-field chemical shift caused by
changes in ring current effects due to altered nucleobase staking.
2. Raman spectroscopy
Raman spectroscopy measures the vibrational frequencies of individual
bonds in the DNA, and hence it is a sensitive measure of chemical bonding
and structure. The Raman spectrum of B DNA exhibits many bands that are
highly sensitive to thermal disordering. Most of the bands can assigned to
specific vibrational modes of base and backbone residues. The temperature
dependent changes can be characterized through analyses of the heat
treatment
of
representative
mononucleotides,
oligonucleotides,
polynucleotides, and native nucleic acids [21-22].
3. Circular dichroism
Circular dichroism spectroscopy measures the absorption of polarized
ultraviolet light by DNA, and shows whether the molecule absorbs more lefthanded or right-handed polarized light [23-24]. A CD spectrometer is an
instrument that records this phenomenon as a function of wavelength.
Modern instruments, however, can generally also record CD as a function of
temperature
or
chemical
environment,
at
several
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wavelengths.
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phenomenon is exhibited in the absorption bands of an optically active
molecule. CD can be used to determine the structure of macromolecules
(including the secondary structure of proteins and the handedness of DNA).
4. UV-Vis spectroscopy
If a newly discovered compound is suspected of targeting cellular DNA, a
battery of simple in vitro experiments can be performed to readily determine
whether the compound physically interacts with DNA. A shift in UV–Vis
absorption of compounds suggests an interaction with DNA [25].
5. Fluorescence (Luminescence)spectroscopy
Fluorescence is the emission of visible light by a substance that has
absorbed light of a different wavelength. In most cases, absorption of light of
a smaller wavelength induces emission of light with a larger (less energetic)
wavelength. Fluorescence contact energy transfer experiments involve the
monitoring of the emission spectrum of a fluorescent compound and
obtaining the excitation spectrum in the presence of DNA [25]. The
appearance of an excitation band absorption wavelength of DNA (260 nm)
indicates a close interaction and transfer of energy between the DNA base
pairs and the small molecule. Although originally thought to be exclusive to
intercalation, certain groove binding compounds are capable of fluorescence
contact energy transfer; therefore other experiments are required to
corroborate the mode of binding [26].
6. Mass spectroscopy
Mono- and oligonucleotides are used as targets when chemical analysis
techniques
spectrometry
such
as
mass
(MALDO-TOF)
spectrometry
are
used
(MS),
to
time-of-flight
study
the
mass
products.
Mononucleotides are available commercially and have found utility in
experiments
to
understand
binding
of
metal
complexes
to
DNA.
Oligonucleotides (oligos) are short strands of DNA (15 - 100) base pairs that
have known sequence and structural properties. Thus oligos are better
models for nuclear DNA because they can be obtained as double stranded
DNA. MALDI-TOF method can measure the mass of the DNA to very high
precision and with great accuracy.
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ii.
11
Physical methods
1. Thermal denaturation study
DNA melting is the process by which the interactions between the strands of
the double helix are broken, separating the two strands of DNA. These bonds
are weak, easily separated by gentle heating, enzymes, or physical force.
DNA melting preferentially occurs at certain points in the DNA [27]. T and A
rich sequences are more easily melted than C and G rich regions. Particular
base steps are also susceptible to DNA melting, particularly T-A and T-G
base steps. These mechanical features are reflected by the use of sequences
such as TATAA at the start of many genes to assist RNA polymerase in
melting the DNA for transcription.
Strand separation by gentle heating, as used in PCR, is simple providing the
molecules have fewer than about 10,000 base pairs (10 kilobase pairs, or 10
kbp). The intertwining of the DNA strands makes long segments difficult to
separate. The cell avoids this problem by allowing its DNA-melting enzymes
(helicases) to work concurrently with topoisomerases, which can chemically
cleave the phosphate backbone of one of the strands so that it can swivel
around the other. Helicases unwind the strands to facilitate the advance of
sequence-reading enzymes such as DNA polymerase.
2. Isothermal titration calorimetry
ITC is a sensitive technique in which compound is titrated into a solution of
DNA, allowing the determination of various binding parameters such as Kd,
enthalpy (ΔH), entropy (ΔS), and the stoichiometry of binding [28]. Although
useful in characterizing whether a compound interacts with DNA, this
technique is rather sensitive to buffer composition, temperature, pH, and
DNA sequence [29]. Therefore, comparisons of DNA interacting molecules
based on literature isothermal calorimetry data can be problematic and
direct experimental comparisons are advised.
3. Viscometry
Although the experiments described above are useful in determining whether
a molecule interacts with DNA, additional experiments are required to
distinguish between intercalation and groove binding. Since intercalators
cause the unwinding and lengthening of DNA, increasing ratios of
intercalator : DNA increase the viscosity of a DNA containing solution [25].
As viscosity is proportional to length, viscosity measurements are very
sensitive to changes in the length of DNA; the application of viscosity
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measurements is limited only by the compound’s aqueous solubility. If a
circular plasmid is used, the viscosity peaks and then declines with
increasing concentrations of the compound, indicative of the DNA changing
from a negative- supercoiled to a relaxed and finally a positive-supercoiled
state [30].
4. Electrochemical methods (Cyclic voltametry)
Electrochemical methods have been used to study the electron transfer
reactions of nucleic acids at mercury electrodes for almost 50 years.
However, recently, the use of solid electrode materials, such as glassy carbon
or carbon paste, enabled the development of new voltammetric methods with
enhanced sensitivity. The development of DNA modified electrodes and DNA
biosensors have allowed the study of the mechanism of interaction with DNA
of metals, drugs and pollutants, and consequently a wide range of analytical
and biotechnological applications. Molecules and ions interact with DNA in
three
significantly
different
ways:
electrostatic,
groove-binding
and
intercalation. These reactions cause changes in the structure of DNA and the
base sequence, leading to perturbation of DNA replication. Electrostatic
interactions are usually non-specific and consist in binding along the
exterior of the dsDNA helix. Groove-binding interactions consist in direct
interaction of the compound with the edges of the base pairs in the major or
minor grooves of dsDNA, extending to fit over many base pairs, and having
very high sequence specificity. Intercalation consists in inserting planar or
nearly planar aromatic ring systems between the base pairs, causing
unwinding and separation of base pairs.
The reduction of cytosine (C) and adenine (A) is irreversible and the cathodic
peak occurs at very negative potentials. The reduction of guanine (G) also
occurs at very negative potentials close to hydrogen evolution: the reduction
product of guanine can be oxidized and the corresponding anodic peak can
be detected in the reverse scan. The most popular method for studies of film
electrochemistry is cyclic voltammetry (CV). The scan rate ν=ΔE/Δt can be
varied from <1mVs-1 to a million or more Vs-1, providing a practical timescale
range from minutes to microseconds to study kinetic events. For the
reversible electrochemical reaction,
O + ne- ↔ R
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The interconversions between oxidized (O) and reduced (R) forms of the
enzyme are fast on the time scale of the voltammogram, as controlled by
scan rate.
5. Electric linear dichroism
Although viscosity can conclusively identify intercalators, electric linear
dichroism can simultaneously distinguish between intercalative and groovebinding modes of interaction [31]. Pulses of electric current align linear DNA
strands such that they are parallel to the electric field vector. The
absorbance of plane polarized light parallel (A║) or perpendicular (A┴) to the
field is quantified in the presence/absence of compound and can be used to
determine the orientation of the small molecule with respect to DNA. If the
absorbance of plane-polarized light parallel to the electric field is less than
the polarized light perpendicular to the field (negative dichroism), this is
suggestive of an intercalative mode of binding. Conversely, a positive
dichroism is indicative of a groove binder. This method has the advantage of
requiring a low drug:DNA ratio (1:10) and is sensitive to anisotropic
interactions. Electric linear dichroism has been used to successfully identify
sequence-dependent interactions of various clinically used DNA-binding
compounds [31]. More impressively, it has been used to identify specific GC
rich sequences that allow the groove binders Hoescht 33258, DAPI, and
berenil to assume a nonclassical intercalative mode of binding [31-32].
6. Atomic force microscopy
DNA in solution does not take a rigid structure but is continually changing
conformation due to thermal vibration and collisions with water molecules,
which makes classical measures of rigidity impossible. Hence, the bending
stiffness of DNA is measured by the persistence length, defined as: "The
length of DNA over which the time-averaged orientation of the polymer
becomes uncorrelated by a factor of e". This value may be directly measured
using an atomic force microscope to directly image DNA molecules of various
lengths. In aqueous solution the average DNA length is 46-50 nm for 140150 base pairs and the diameter 2 nm, although can vary significantly. This
makes DNA a moderately stiff molecule. The persistence length of a section
of DNA is somewhat dependent on its sequence, and this can cause
significant variation. The variation is largely due to base stacking energies
and the residues which extend into the minor and major grooves.
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The resolution of AFM images depends, in large part; on the size of the tip. A
tip sharper than the smallest feature to be imaged will generally provide the
best resolution. Under proper conditions, images showing individual atoms
can be obtained. Thus a major feature of AFM is the ability to acquire threedimensional
images
with
angstrom-
or
nanometer-level
resolution.
Furthermore, imaging can be conducted without staining, coating, or other
preparation, and under physiological conditions. Striking images of surfaces,
biomolecules such as DNA or polymer–DNA complexes, can be obtained [3334]. Newer developments in AFM methods enable chemical and mechanical
information to be obtained. By attaching specific chemical groups to an AFM
tip, the spatial arrangement of functional groups on a surface can be
mapped. Also, because AFM is based on interaction between the tip and
sample as well as surface topography, local mechanical properties, such as
stiffness and friction can be determined [35].
7. Gel electrophoresis
Gel electrophoresis, separate the fragments of DNA according to their size,
where DNA is passed through a gel in the presence of an electric field, and
there by separated according to its size, shape, and electric charge. Gel is
nothing more than a three-dimensional array of tiny, randomly oriented
fibers, like the fibers in a grass mat that you wipe your feet on before going
into the house. It is easy to see why a typical gel should be highly porous to
small molecules such as DNA or protein: they can move easily through the
gel by passing through the water spaces between the gel fibers. Some small
molecules can move only slowly through a gel by diffusion, if they are
uncharged. But DNA and protein both carry a net electric charge, and so
they can move quickly through a gel in the presence of an electric field.
The interaction of plasmid DNA in presence of complexes can be studied to
determine the efficiency with which it sensitizes DNA cleavage. This can be
achieved by, monitoring the transition from the naturally occurring,
covalently closed circular form (Form I) to the open circular relaxed form
(Form II). This occurs when one of the strands of the plasmid is nicked, and
can be determined by gel electrophoresis of the plasmid. Extended
interaction results in a buildup of nicks on both strands of the plasmid,
which eventually results in its opening to the linear form (Form III). When
circular plasmid DNA is subjected to gel electrophoresis, relatively fast
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migration will be observed for the supercoiled form (Form I). Form (II) will
migrate slowly and Form III will migrate between Form II and Form I [36-37].
8. Surface plasmon resonance (SPR) biosensor technology
Surface plasmon resonance (SPR) biosensor technology has recently become
an established method of measuring a variety of bio molecular interactions
in real time. It is capable of characterizing binding reactions without labeling
requirements. In a typical SPR experimental set-up, incident light is reflected
from the internal face of a prism in which the external face has been coated
with a thin metal film at a critical angle, the intensity of the reflected light is
lost to the creation of a resonant oscillation in the electrons at the surface of
the metal film [38]. Since the critical angle is dependent on the refractive
index of the material present on the metal surface, this real-time method has
been used to measure molecular interactions at solid-liquid interface. One
reactant, referred to as the ligand, is immobilized to the sensor surface and
the other reactant, referred to as the analyte, flows past this surface in
solution. When the analyte and the ligand interact to form a complex, a
response is generated and monitored in real-time. SPR biosensors measure
the change in refractive index in the vicinity of the surface of sensor chips to
which ligands are immobilized [39]. Because the changes in the refractive
index are proportional to the changes in the adsorbed mass, the SPR
technology
allows
detection
of
analytes
interacting
with
the
ligand
immobilized on the sensor chip. It can thus be used to study the interactions
of any biological system from oligonucleotides, oligosaccharides, proteins,
and lipids to small molecules, viral particles, and bacterial cells. More
fundamentally, the technique allows the direct observation of association
and dissociation rate constants that contribute to the overall binding
affinity. The recent development of SPR-based biosensor technologies has
made it possible to directly monitor the binding of low molecular mass
compounds to immobilized macromolecules and thus allowed the study of
fast molecular interaction kinetics and the evaluation of binding constants
for DNA-drug interactions in free solution [39-43].
1.4 Various DNA binding agents
The quest to understand specific interactions between drugs and nucleic
acids dates back a long time - more than 40 years. Even though the concept
of gene targeting could not be explicitly formulated until much later, there
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were early realizations that DNA could provide a fine receptor for drugs. The
publication in 1961 by Leonard Lerman of the intercalation hypothesis is a
major turning point in the history of drug binding to DNA [7]. Such agents
includes metallopeptides [44-49], where the use of transition metal ions in
the generation of structured, nucleic acid-binding peptides provides several
distinct advantages including: A) the ability to construct complexes with
well-defined geometries and B) the inclusion of metal-centered redox
properties enabling the final complex to mark a location of binding through
an act of DNA or RNA strand scission [50-51].
Metallopeptides derived from Ni(II), Cu(II), or Co(III) complexes of GlycineGlycine-Histidine derived peptides create unique and reactive agents
through which understanding of nucleic acid structure and recognition
through the development of affinity cleavage strategies and as stand-alone,
low-molecular-weight complexes [52-53]. Metal-salen complexes can be used
as potential DNA binding agents. A notable example illustrating the binding
affinity of a cationic nickel-salen that covalently couples to accessible
guanine residues in DNA [54]. By varying the metal and ligand substituents,
salen complexes can be shown to either cleave the phosphoribose backbone
of DNA or alkylate the nudeobase guanine within DNA and RNA under
control of a range of different redox partners and with various structural
specificities [53].
Many of the salen derivatives additionally offer practical alternatives to the
most popular probes of nucleic acids that are based on metal complexes
such as FeEDTA [55], Cu(l,10-phenanthroline) [56], NiCR [57], and those
containing rhodium [58-59] or ruthenium [60]. Some complexes of rhodium
and ruthenium particularly, dipyridophenazine has utilized a number of
metallointercalators to study long-range electron transfer and oxidation
mediated in DNA [61-66].
Of course, novel platinum anticancer drugs are included in the unique group
of DNA binding agents as they are highly effective for the treatment of
testicular and ovarian cancer and used in combination regimens for a variety
of other carcinomas, including bladder, small lung tumors and those of head
and neck [15, 49, 67]. Extensive literature can be found on behalf of agents,
which can mediate chemical detection of nucleic acid [68-69] one of the most
important agents is EtBr which is used as a probe to quantify the DNA [7071].
Department of Chemistry (SPU)
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17
Some well-known DNA binding organic drugs
Another major class of small molecules is potent antimicrobials that bind to
DNA plays important roles in drug development [72-76] including netropsin
[64,65], DAPI (D',6-diamidino-2-phenylindole) [34, 69], berenil (also known
as diminazene; l,3-bis-D-amidinophenyl)triazene) [77], pentamidine A, 5-bisD-amidinophenoxy)pentane) [77-78], dicationiccarbazoles and analogs [7981], dicationic furans [82-86], fluoroquinolones and analogous [87-93], etc.
1.5 Fluoroquinolones
1.5.1 General aspects and characteristics of quinolones
Quinolones comprise a relatively large, growing and most interesting group
of antibacterial drugs which have made a major impact on the field of
antimicrobial chemotherapy, particularly in the past few years [94-101]. The
evolution of quinolones actually emanated from the discovery of nalidixic
Department of Chemistry (SPU)
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18
acid [102] in 1962 as a by-product of antimalarial research, the first
representative of the quinolones which was found effective against some
Gram-negative microorganisms and having pharmacokinetic properties for
treating urinary tract infections (UTIs).
This is because they potentially offer many of the attributes of an ideal
antibiotic, combining high potency, a broad spectrum of activity, good
bioavailability, oral and intravenous formulations, high serum levels, a large
volume of distribution indicating concentration in tissues and a potentially
low incidence of side-effects. More researches have attempted to make these
potential attributes real. However, following the introduction of nalidixic acid
for the treatment of uncomplicated UTIs caused by enteric bacteria, the
quinolones
became
a
neglected
group
of
antimicrobials
until
the
development of the fluoroquinolones in the 1970s and 1980s. The
fluoroquinolones have an extended spectrum of activity and improved
pharmacokinetics compared with the earlier compounds. In last two
decades, the quinolones moved from a relatively small and unimportant
group of drugs used predominantly for the treatment of UTIs, to molecules
with potent activity against a wide spectrum of significant bacterial
pathogens [103]. Recently, there has been a considerable increase in the
number of agents that are in development, and to date over 10,000
molecules have been patented. The subsequent four decades have seen the
identification of many thousands of molecules, now generically classified as
‘the quinolones’, although strictly, these are derivatives of either the 4quinolone or 1, 8-naphthyridine ring structures. Therefore, the quinolones
cover the modern era of antibiotic drug discovery. Quinolones have been not
only widely used, but also intensively studied and, as such, have probably
added more to our knowledge of antimicrobial science than any other class
of antibiotics or antimicrobial chemotherapeutic agents.
1.5.2 Generations and development of quinolones
Based on the 4-quinolone nucleus, the quinolones comprise a relatively large
and expanding group of synthetic compounds. An alkaloid having quinolone
structure was first prepared by Price [104] but it possessed no biological
activity. In 1960, Barton et al. [105] isolated 6-chloro-1H- ethyl-4-oxoquinoline-3-carboxilic acid during antimalarial research, which showed
antibacterial activity. In 1962, during the process of synthesis and
Department of Chemistry (SPU)
Chapter 1
purification
of
chloroquine
(an
antimalarial
19
agent),
a
naphthyridine
derivative, nalidixic acid, was discovered which possess bactericidal activity
[102]. However, its clinical use was limited to the treatment of UTIs caused
by
the
majority
of
Gram-negative
bacteria,
with
the
exception
of
Pseudomonas aeroginosa. The clinical usefulness of nalidixic acid, in the
treatment of other infections than UTIs, was limited by its low serum
concentrations and high minimum inhibitory concentrations (MIC 4–16
mg/L) [106].
Common structure of 4-quinolones
Thereafter, novel compounds of this family, such as oxolinic acid, piromidic
acid, pipemidic acid, and cinoxacin were synthesized and introduced into
clinical practice, although the clinical indication for these quinolones still
remained only for UTIs [107-108]. These early agents, however, proved
invaluable in the treatment of uncomplicated UTIs, such as cystitis. Nalidixic
acid has several structural features retained by the newer compounds, and
is based on a 4-oxo-1,8-naphthyridin-3-carboxylic acid nucleus. Two major
groups have been developed from the basic structure: quinolones and
naphthyridones [109-112]. The presence of nitrogen at position 8 identifies
the naphthyridones, a carbon and associated group at position 8 identifies
the quinolones. The quinolones and naphthyridones were further improved
by the addition of groups to the N-1, C-5, C-6 and C-7 positions of their
respective basic molecules. Until the development of flumequine, the first
monofluoroquinolone in 1976, none of the earlier compounds had offered
any significant improvements over nalidixic acid. Flumequine was the first
compound to be developed with a fluoro- group at position 6, and gave the
first indications that modifications of the basic chemical structure could
improve Gram-positive activity [103]. Its range of activity embraced the
enterobacteriaceae, including some strains that were resistant to nalidixic
acid with useful activity against uncomplicated gonorrhoea, albeit with a
two- or three-dose regimen. In 1978 norfloxacin, a 6-fluorinated quinolone
Department of Chemistry (SPU)
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20
with a piperazinyl side-chain at position 7 was developed. Norfloxacin had a
longer half-life than the earlier compounds (3–4 h), less protein binding
(50%) and improved Gram-negative activity [113]. The addition of a fluorine
atom at position 6 was one of the earliest changes of the basic structure.
This single alteration provides a more than 10-fold increase in gyrase
inhibition and up to 100-fold improvement in MIC. During the 1980s, a great
number of fluoroquinolones were developed. In addition to fluorine atom at
the C-7 position, a cyclopropyl group was introduced to the N-1 position and
is best exemplified by ciprofloxacin, which was first synthesized in 1983.
This increases the potency of the drug and many subsequent quinolones
have a cyclopropyl group. The benzopyridone nucleus (quinolone) proved to
be more responsive to chemical manipulation which made in order to
enhance antibacterial potency. Subsequent discovery of fluorine atom and
piperazinyl ring on the quinolone ring namely norfloxacin, ciprofloxacin,
ofloxacin, prulifloxacin revolutionized the chemistry of fluoroquinolones
[103, 107-112]. These agents showed potent activity against Gram-negative
bacteria, but not against the Gram-positive bacteria or anaerobes. In the
1990s, further alterations of the quinolones resulted in the discovery of novel
compounds that not only showed potent activity against Gram-negative
bacteria but also against the Gram-positives.
A number of other structural manipulations have been tried to improve the
anti-Gram-positive activity of fluoroquinolones. One of the first additions
was an NH2 group at position C-5, which resulted in a general increase in
anti-Gram-positive activity [103, 107-115]. This is seen with sparfloxacin
which otherwise has a very similar structure to ciprofloxacin. Sparfloxacin
also has fluorine at position C-8, a piperazine at position C-7 and is
alkylated. Grepafloxacin is also substituted at position C-5 but by a CH3
group
which
improved
anti-Gram-positive
potency
compared
with
ciprofloxacin [116]. Other new quinolones containing 7-piperazinyl group are
gatifloxacin, lomefloxacin and levofloxacin (the (S)-enantiomer of ofloxacin).
Gatifloxacin is a racemic compound that bears C-7 3-methylpiperazinyl and
C-8 methoxy substituents. Gatifloxacin is active against penicillin-resistant
S. penumoniae and has proven highly effective in the treatment of lower
respiratory tract infections. Pyrrolidine rings (five-membered) are also
common substituents at position 7 and are associated with enhanced
potency against Gram-positive bacteria. However, this group is associated
Department of Chemistry (SPU)
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21
with low water solubility and low oral bioavailability, so in-vivo activity may
be compromised. Introduction of methyl groups on the pyrrolidine ring helps
to overcome some of these physical properties. Naphthyridine derivatives,
tosufloxacin
and
gemifloxacin
are
example
of
the
advantages
and
disadvantages associated with a pyrrolidine ring at position 7 [103, 117]. The
addition of azabicyclo groups onto position 7 has resulted in agents
(moxifloxacin and trovafloxacin) with significant anti- Gram-positive activity,
marked lipophilicity and half-lives of >10 h [118-119]. Sitafloxacin is another
new fluoroquinolone that is in limited development due to photosensitivity.
Unique structural features of sitafloxacin, which is being developed as a
single enantiomer, include a novel aminopyrrolidine substituent at C-7 and
a fluorocyclopropyl group at N-1 [103]. Manipulation of the group at position
8 has also been shown to play a role in altering oral pharmacokinetics,
broadening the spectrum of activity and reducing the selection of mutants
[120-123]. Whilst alkylation has been shown to increase further anti-Grampositive activity, it also improves tissue penetration and increases the halflife by increasing lipophilicity, as with grepafloxacin, levofloxacin and
sparfloxacin. In addition, some of the new compounds, such as trovafloxacin
(having 2, 4-difluorophenyl group at position 1), also showed promising
activity against the anaerobes. Thus, continuous efforts were directed to
further modify the quinolone pharmacophore with more complex newer
fluoroquinolones, namely danofloxacin, pazufloxacin, clinafloxacin and
prulifloxacin. Recently, non-fluorinated quinolones, such as garenoxacin
have been developed, which further opens novel avenues in the development
of quinolone antibiotics [124]. The targets in fluoroquinolone research during
the last few years include improving the pharmacokinetic properties,
increasing the activity against Gram-positive cocci and anaerobes and
against fluoroquinolone resistant strains, and improving activity against
non-fermentative Gram-negative species [125-127].
1.6 Biochemistry of Nickel, Cadmium and Vanadium
1.6.1 Nickel and its biochemistry
Nickel is a metallic element, (relative atomic mass 58.69) 23rd most
abundant element of the earth crust, is found in the first transition series
group 10 of the Periodic Table. There are 31 isotopes of nickel ranging from
48Ni
to
78Ni.
Five of these are known natural isotopes, of which
Department of Chemistry (SPU)
58Ni
Chapter 1
(68.007%) and
60Ni
22
(26.223%) are the most abundant. In addition seven
artificial isotopes are known with half-lives ranging from milliseconds to
hundreds of years. An important isotope for biophysical studies is
61Ni
which
has a nuclear spin of 3/2 [128].
The role of nickel in bioinorganic chemistry has been rapidly escalating [129131]. Additionally, nickel complexes of biological interest have been reported
with the most structurally characterized acting as antiepileptic [132],
anticonvulsant [133] agents or vitamins [134] or showing antibacterial [135153], anticancer/antiproliferative [154-163], antifungal [135, 164-169],
antiviral [170-171] and antimicrobial [145, 153, 172-174] activity. The
interaction of Ni(II) complexes with DNA has been mainly dependent on the
structure of the ligand exhibiting intercalative behavior [175-185] and/or
DNA cleavage ability [72, 183-190].
1.6.2 Cadmium and its biochemistry
Cadmium (atomic number 48) the soft, bluish-white metal, is chemically
similar to the two other metals in group 12, zinc and mercury. Similar to
zinc it prefers oxidation state +2 in most of its compounds. There are 52
isotopes of cadmium. Naturally occurring cadmium is composed of 8
isotopes. For two of them, natural radioactivity was observed, and three
others are predicted to be radioactive [128]. About three-quarters of all the
cadmium is used in batteries, predominantly in rechargeable nickelcadmium batteries.
Cadmium is a highly toxic heavy metal with half-life time of about 10 years
in human beings. It accumulates predominantly in the kidneys as well as in
liver, which are the critical target organs [191]. Biological role of cadmium in
an animal organism is unknown. It is designated as a carcinogen in humans
and rodents [192].
However, the concentrations of Cd required to induce overt DNA damage are
usually very high [193-195]. The damage of nucleic acids is due to direct or
indirect effects of cadmium. Cadmium induces, for example, an oxidative
DNA damage leading to DNA strand-breaks, DNA-protein cross-linking and
inhibition of DNA repair [196].
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23
1.6.3 Vanadium and its biochemistry
Vanadium (atomic number 23) is a soft, silvery gray, ductile transition metal.
The formation of an oxide layer stabilizes the metal against oxidation. The
chemistry of vanadium is noteworthy for the accessibility of four adjacent
oxidation states. The common oxidation states of vanadium are +2 (lilac), +3
(green), +4 (blue) and +5 (yellow). Vanadium(II) compounds are reducing
agents, and vanadium(V) compounds are oxidizing agents. Vanadium(IV)
compounds often exist as vanadyl derivatives which contain the VO2+ center.
Vanadium compounds, which are best known as insulin mimetics, have also
shown anticancer effects. These compounds, specifically the vanadate and
peroxovanadium complexes, are competitive inhibitors of protein tyrosine
phosphatases (PTP). Vanadate acts as a transition-state analogue by binding
reversibly to a thiol group in the catalytic domain, while peroxovanadium
complexes oxidize a critical cysteine residue in the catalytic domain. In
serine/threonine phosphatases, vanadate binds a hydroxyl group in the
active site while the peroxovanadium complexes are inactive here, in the
absence of the cysteine. Peroxovanadium complexes have demonstrated an
ability to block the cell cycle at the G2-M transition (G2) growth phase 2, a
preparatory phase for mitosis; M) mitosis, a period of active cell division),
and this seems to be mediated by the inhibition of a PTP whose function is
essential for the progression to mitosis [197-198]. This blockage may be
related to their cytotoxic effects.
1.7 Applications of coordination compounds as metalloantibiotics
Antibiotics can interact with a variety of biomolecules, which may result in
inhibition of the biochemical or biophysical processes associated with the
biomolecules. This can be illustrated in the interaction of the peptide
antibiotic polymyxin with glycolipids which affects membrane function [199],
in the intercalation of the anthracyclines (ACs), fluoroquinolones into DNA
base pairs which stops gene replication [200-201], in the imbedding of the
lipophilic antibiotic gramicidin [202] and the insertion of the amphiphilic
antibiotic protein colicin A into cell membrane [203] which disturb normal
ion transport and trans-membrane potential of cells, in the inhibition of
transpeptidase by penicillin which affects cell wall synthesis [204-206], and
Department of Chemistry (SPU)
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24
the inhibition of aminopeptidase by bestatin, amastatin, and puromycin
which impairs many significant biochemical processes [207].
Although most antibiotics do not need metal ions for their biological
activities, there are a number of antibiotics that require metal ions to
function properly or effectively, such as bleomycin (BLM), streptonigrin (SN),
and bacitracin, fluoroquinolones [208]. In short the coordinated metal ions
in these antibiotics play an important role in maintaining proper structure
and/or function of these antibiotics. Removal of the metal ions from these
antibiotics can cause changes in structure and/or function of these
antibiotics. Similar to the case of ‘‘metalloproteins’’ these antibiotics are
dubbed ‘‘metalloantibiotics’’. Metalloantibiotics can interact with several
different kinds of biomolecules, including DNA, RNA, proteins, receptors,
and lipids, rendering their unique and specific bioactivities. In addition to
the
microbial-originated
metalloantibiotics,
many
metalloantibiotics
derivatives and metal complexes of synthetic ligands also show antibacterial,
antiviral, and antineoplastic activities.
Bleomycin (BLM, also known as Blenoxane) was first isolated as a Cu2+
containing glycololigo peptide antibiotic from the culture medium of
Streptomyces verticullus [209], and was later found to be also an antiviral
and anticancer agent [210]. As the antibiotic mechanism of BLM depends on
metal ions, it is the most extensively studied metalloantibiotic from several
different viewpoints, such as its metal binding property, structural studies
with a variety of spectroscopic methods, mechanistic study of its oxidative
DNA cleavage, investigation of its structure-function relationship, and its
use as a non-heme model for investigation of dioxygen activation and DNA
recognition/cleavage [211]. There are a few BLM-like antibiotics which
exhibit similar physical, structural, and biochemical characteristics as BLM
[212].
Aureolic acids, these antibiotics contain a metal-binding β-ketophenol
chromophore,
a
highly
functionalized
aliphatic
side
chain,
and
a
disaccharide and a tri-saccharide chains important for DNA binding and
inhibition of DNA transcription. A divalent metal ion, such as Mg2+, Co2+,
Zn2+, or Mn2+, is required for aureolic acid to bind to a double helical DNA to
form a (drug)2–metal–(DNA)2 ternary complex [213-214]. The metal–(drug)2
complex in the ternary complex is bound to DNA in the minor groove with a
high preference to GC sites and a length of approximately six base pairs.
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Streptonigrin (SN, also known as rufochromomycin and bruneomycin) is a
metal-binding quinine containing antibiotic produced by Streptomyces
flocculus [215]. SN is known to bind different transition metal ions to
function properly [216-217]. A redox active metal ion such as Fe and Cu is
required for this antibiotic to exhibit full antibiotic and antitumor activities
[218-219]. The redox-active Fe and Cu complexes have been shown to
accelerate SN mediated DNA scission in the presence of NADH, thus
enhance the anti-tumor activity of this antibiotic [220-223].
Anthracycline (AC) antibiotics are produced by Streptomyces species. Soon
after their discovery, they were found to exhibit a wide spectrum of
antineoplastic activity toward both solid and hematologic tumors and
cancers [222-224]. In addition, an AC antibiotic has been found to exhibit
antifungal
activity
[225].
Despite
their
severe
cardiotoxicity
(e.g.,
cardiomyopathy) and other side effects, these antibiotics have been widely
used as dose-limited chemotherapeutic agents for the treatment of human
cancers such as acute leukemia. ACs are known to bind various metal ions,
including transition metal, main group, lanthanides, and uranyl ions [226].
A number of articles reported that some metal ions, e.g., Fe2+/3+, Cu+/2+, Pd2+,
Pt2+ and Tb3+, play an important role in altering the biochemical properties of
ACs [227-228]. These studies point a new direction in the pursuit of
chemotherapeutic efficacy and lowering toxicity of these antibiotics. The
binding of metal ions may cause a significant influence on the redox
property of these drugs in their Yb3+ complexes [229].
The antibiotic activities of the platinum complexes cis-diamminedichloro
platinum and cis-PtIVCl6(NH4)2 were found serendipitously by Barnett
Rosenberg to cause dramatic elongation of E. coli during a study of the
influence of electric fields on the growth of the bacterium by the use of a
platinum electrode in a buffer solution containing NH4Cl [67]. Upon
introduction of DNA, cisplatin binds to the N7 nitrogen of two adjacent
guanidine bases or guanidine–adenine bases in the major groove, or two
proximal guanidine bases on different strands in the minor groove which
distorts the DNA structures by bending the helix by 40–60° and a helical
twist of 25–32°. The DNA binding mode of cisplatin cannot be achieved by its
stereoisomer ‘‘transplatin’’ [230]. The lability of the Pt–Cl bond still allows
nucleophilic substitution to occur in transplatin which can result in DNA
binding. However, the DNA binding of transplatin is significantly different
Department of Chemistry (SPU)
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26
from that of cisplatin, wherein cross-strand linkage becomes predominant.
The DNA binding and antitumor activities of the cisplatin analogues can be
found from literature [230-232].
Interactions of quinolones with DNA and the role of metal ions in these
processes:
Bacterial DNA topology is controlled by three enzymes, DNA gyrase
introduces negative supercoiling; DNA topoisomerase I counters the action of
gyrase to prevent the accumulation of excess supercoiling; and DNA
topoisomerase IV plays a central role in the resolution of interlinked,
replicated daughter chromosomes. Numerous classes of compounds have
been demonstrated to interfere with both prokaryotic and eukaryotic
enzymes. Among these, very active and widely prescribed drugs are currently
being utilized for the treatment of bacterial infections and human cancers
[233]. DNA gyrase and DNA topoisomerase IV are both sensitive to the 4quinolone class of antibacterial compounds in vitro. The activity of
quinolones is due to the inhibition of the supercoiling of DNA catalyzed by
the enzyme DNA gyrase. Contradictory reports have appeared in the
literature
on the molecular details of drug/DNA
and drug/enzyme
interactions [100, 234-261]. Shen and coauthors have proposed drug/DNA
models which imply hydrogen-bond type interactions between the DNA
unpaired bases and the quinolone, as well as a stacked dimerization of the
drug [244, 249-250]. Their results were also not quite consistent with the
previously reported fact that nalidixic acid binds to single-stranded DNA
only in the presence of an excess of copper ions [262]. The model has been
modified and includes a possible interaction between the C-7 substituent
and the quinolone pocket on the B subunit of DNA gyrase [241].
Many authors have stressed the role of magnesium in the quinolone/DNA
interaction [263-267]. It was suggested that Mg(II) acts as a bridge between
the quinolone and the phosphate group of the DNA, and that this complex is
stabilized by stacking interactions between the condensed rings of the drug
and the DNA bases in a single-stranded region or a distorted B-form in
plasmid. In the subsequent study it was confirmed that DNA-affinity of the
quinolone, modulated by Mg(II), plays an important role in poisoning the
cleavable gyrase/DNA complex and, consequently, in eliciting antibacterial
activity by this family of drugs. The results obtained with different 6substituted compounds support the idea that position 6 of the drug, besides
Department of Chemistry (SPU)
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27
playing a pharmacokinetic role, is involved in recognition of the enzyme
pocket. Llorente and coworkers [268] have proposed another model based on
the intercalation of quinolone into the double helix of DNA. However, the
results reported by Hurley et al. in their parallel study of quinobenzoxazines
and norfloxacin have shown that in the presence of Mg(II), only the former
are able to form a stable intercalated complex with DNA [269]. Interest in the
rational design of new transition metal complexes which bind and cleave
duplex DNA with high sequence or structure selectivity is growing [270].
It was later found that norfloxacin, which can only play an external binding
role,
was
able
to
modulate
the
photochemical
reaction
of
the
quinobenzoxazines on DNA [271]. Afterword some studies have also been
performed where an important role of metal ions in the mechanism of action
of these drugs was again proposed. From a theoretical/experimental study
on the structure and activity of certain quinolones and the interaction of
their Cu(II) complexes on a DNA model, it was suggested that the
intercalation of the quinolone complexed to a metal is an important step in
these processes [272]. The conformational equilibria of DNA gyrase A
(subunit of the enzyme) in the presence of Mg(II) and ciprofloxacin were
studied. It was proposed that the magnesium mediated quinolone binding to
the enzyme might be involved in the mechanism of action of this family of
drugs [273]. We can conclude that the mode of action of these drugs and
related processes were extensively studied in the past. The topic is extremely
important due to the fact that several quinolones are used in clinical
practice. But obviously there are still several questions to be answered.
Because of the increase in bacterial resistance toward many currently used
antibiotics in recent years, further development of new antibiotics has
become an urgent mission. Better understanding of the structure, function,
and mechanism of existing metalloantibiotics and the mechanism of
antibiotic resistance will lead to better design of metal complexes for this
mission. As the chemical properties of metal ions can vary significantly and
can also be further fine-tuned by proper design of drug ligands for targeting
different biomolecules and bio components, new generations of various
‘‘metalloantibiotics’’ isolated from natural resources or obtained via chemical
syntheses and/or modifications that exhibit more effective antiphrastic,
antibacterial, antiviral, and anti-tumor activities can be foreseen. According
to these facts, the further aim of this study was to determine biological
Department of Chemistry (SPU)
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activity of the structurally related complexes. Metal–quinolone compounds
were thus tested for potential antibacterial activity and DNA cleavage
activity.
1.8 Literature survey
Metal ions play a key role in the actions of some synthetic and natural
antibiotics and are involved in specific interactions of these molecules with
proteins, nucleic acids and other biomolecules. It is known that the
magnesium quinolone complex interacts with DNA and impairs its function
and due to this reason quinolones are also classified as metalloantibiotics
[72].
Smith and Ratcliffe (1986) studied the effect of pH value and magnesium on
the antibacterial activity of quinolone preparations [274]. Neu and Chin
(1987) studied the in-vitro activity of quinolone antimicrobial agents, S25930 and S-25932 [275]. Mendoza-Díaz et al. (1987) reported the crystal
structures of [Cu(Phen)(Nal)]+ and [Cu(Bipy)(Nal)]+ [276]. Smith et al. (1988)
reported that the divalent magnesium and calcium cations might affect
susceptibility test results for the quinolone compounds [277]. Niu and Neu
(1989) performed the comparative in vitro activity of fluorinated 4-quinolone,
QA-241 and reported that the activity was less at an acidic pH and in the
presence of high Mg2+ concentration against various bacteria [278]. Gugler
and Allgayer (1990) studied the effects of antacids on the clinical
pharmacokinetics of quinolone antibiotics and reported that the absorption
of ciprofloxacin and ofloxacin is reduced by 50 to 90% in the presence of
aluminum and magnesium hydroxide containing antacids [279]. Valisena et
al. (1990) studied the relevance of ionic effects on norfloxacin uptake by
Escherichia coli and reported that the presence of Na+ or K+ ions does not
affect the results to an appreciable extent, whereas divalent ions cause a
dramatic decrease in drug incorporation [280]. Jordis et al. reported the
difluoroboric quinolone complex [281]. A compound of cobalt(II) with the
formula Na[Co(cx)3].6H2O was isolated by C. Chulvi et al. [282].
Campbell et al. (1992) reported the interactions of norfloxacin with antacids
and minerals and concluded that the efficacy of norfloxacin treatment may
be compromised when it is taken concurrently with preparations containing
ferrous sulphate, zinc sulphate, aluminium hydroxide and magnesium
hydroxide ions [283]. Canton et al. (1992) studied in vitro activity of
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sparfloxacin and reported that increasing in the magnesium concentration,
increase the MIC by 2 and 10 folds, depending on the organism [284].
Shimada et al. (1992) studied the complexes of lomefloxacin (LFLX) with Al3+
and Mg2+ [285]. Riley et al. (1993) characterized the complexes of
lomefloxacin and norflaxacin with aluminum ions by nuclear magnetic
resonance spectroscopy [286]. Mendoza-Díaz et al. (1993) prepared some
mixed-ligand complexes of copper(II) with cinoxacin or oxolinic acid and (N--N)
donors,
and
also
reported
the
crystal
structure
of
[Cu(phen)(Cnx)(H2O)]NO3·H2O [287]. Ruiz (1993) reported Ni(II) and Zn(II)
complexes with cinoxacin [288]. Marshall and Piddock (1994) reported the
complexes of magnesium or calcium cations with quinolones [289].
Gao et al. (1995) reported the synthesis, characterization and antibacterial
activity of Fe(III), Co(II), and Zn(II) complexes with norfloxacin [290]. Teixeira
et al. (1995) reported complexes of ciprofloxacin with magnesium or
aluminum and proposed the mechanism of their interaction on the
gastrointestinal absorption [291]. el Walily et al. (1996) reported the
spectrophotometric and spectrofluorimetric estimation of ciprofloxacin and
norfloxacin by ternary complex formation with eosin and palladium(II) [292].
Mendoza-Diaz et al. (1996) studied the complexation equilibria of the
antibiotic
anions
nalidixate
and
cinoxacinate
with
[Cu(phen)]2+
and
[Cu(bipy)]2+ [293]. Wallis et al. (1996) synthesized and characterized complex
of copper(II) with ciprofloxacin and bipyridyl by X-ray structural and
potentiometric studies [294]. Turel et al. (1996) reported an adduct of
magnesium sulfate with ciprofloxacin [295]. Turel et al. (1996) studied
complex formation between some metal ions [Ca(II), Co(II), Ni(II), Cu(II),
Zn(II),
Al(III)
and
Fe(III)]
and
ciprofloxacin
by
potentiometric
and
spectroscopic methods in solution [296]. The thermal behaviour of copper(II)
complexes of ciprofloxacin was studied by Turel et al. (1996) [297]. Turel et
al.
(1996)
reported
the
crystal
structure
of
norfloxacin
and
its
(nfH2)(nfH)[CuCl4]Cl.H2O and (nfH2)(nfH)[ZnCl4]Cl.H2O derivatives [298].
Alvarez et al. (1997) have undertaken a systematic study of the nature of
quinolone metal complexes (where M is either Cu, Co, or Ni) formed by
electrospray ionization and laser desorption/ion-molecule reactions to
evaluate the analytical utility of metal complexation as an alternative to
conventional ionization via protonation [299]. Crystal structure
and
antimicrobial activity against different microorganisms of the bismuth(III)
Department of Chemistry (SPU)
Chapter 1
30
compound with ciprofloxacin was reported by Turel et al. [300], in addition
to that same group have reported the crystal structure of bis(acetato-O)(7chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylatoO3,O4)boron compound (1997) [301]. Veiopoulou et al. (1997) applied
terbium sensitized fluorescence for the determination of fluoroquinolone
antibiotics pefloxacin, ciprofloxacin and norfloxacin in serum [302]. Ruiz et
al. (1997) reported the potentiometric and spectroscopic studies of cobalt(II),
nickel(II), copper(II), and zinc(II) complexes with cinoxacin in addition to that
crystal structures of new Cu(II) and Ni(II) cinoxacin complexes were also
reported [303]. Ruiz et al. (1998) reported the antibacterial studies of
cinoxacin complexes with Cd2+, Co2+, Cu2+ ions [304]. Sissi et al. (1998)
reported the Mg2+ mediated binding of 6-substituted quinolones to DNA and
evaluated the binding constant for the ternary drug-DNA-Mg2+ complex
[305]. Crystal structure of (cfH2)2[Bi2Cl10]·4H2O and antibacterial studies was
reported by Turel et al. (1998) [306].
Djurdjevic and Jelikic-Stankov (1999) studied the solution equilibria
between aluminum(III) ion and ofloxacin [307]. Egorova et al. (1999)
determined pipemidinic acid using the europium chelate fluorimetrically
[308]. Sakai et al. (1999) carried out the comparison of the complexation of
fluoroquinolone antimicrobials (levofloxacin, ciprofloxacin and lomefloxacin)
with metal ions (Al3+, Ca2+ and Mg2+) by nuclear magnetic resonance
spectroscopy [309]. Turel et al. (1999) reported the crystal structure of
copper(II)
ciprofloxacin
complex
[Cu(cf)(H2O)3]SO4.2H2O
[310].
NMR
investigation of the copper(II) ciprofloxacin system in acidic and basic media
was carried out by Turel et al. [311]. Duran Meras et al. (2000) carried out
the complexation of antibacterial quinolonic acid and cinolonic derivatives
with Zn(II) and Al(III) and determined the presence of quinolonic acid in
human urine by fluorimetric technique [312]. Robles et al. (2000) studied the
interaction of certain free quinolones and their Cu(II)-complexes theoretically
and experimentally and reported the structure and activity of certain
quinolones on a DNA model [272]. Teixeira et al. (2000) carried out the
thermodynamic study of complexation of ciprofloxacin and lomefloxacin with
aluminium ion [313]. Turel et al. (2000) reported the biological activity of
some magnesium(II) complexes of quinolones [314]. Zhang et al. (2000)
synthesized and characterized the solid complexes of Ni(II), Cu(II) and Zn(II)
nitrates with norfloxacin [315].
Department of Chemistry (SPU)
Chapter 1
31
Kim et al. (2001) reported the antitumor activity of quinolones (flumequine,
nalidixic acid or oxolinic acid)-platinum(II) conjugates [316]. Macias et al.
(2001) reported the complexes of Ni(II) and Cu(II) with ofloxacin [317]. Sissi
et al. (2001) reported that “Ciprofloxacin affects conformational equilibria of
DNA gyrase A in the presence of magnesium ions” [273]. Uivarosi et al.
(2001) reported the structure and antimicrobial activity of complexes of
Cd(II) and Hg(II) with norfloxacin and ofloxacin [318]. Lopez-Gresa et al.
(2002) studied the interactions of metal ions (Cd2+, Co2+, Zn2+, Ni2+) with two
quinolone antimicrobial agents (cinoxacin and ciprofloxacin) [319]. Macias et
al. (2002) reported complexes of Co(II) and Zn(II) with ofloxacin [320]. Yang et
al. (2002) reported the synthesis and spectroscopic characterization of
complexes of trivalent lanthanide ions Eu(III) and Tb(III) with ofloxacin [321].
Ramirez et al. (2003) reported the degradation of single stranded nucleic
acids by the chemical nuclease activity of the metal complex [Cu(phen)(nal)]
[322]. Yang et al. (2003) synthesized solid complexes of pipemidic acid with
rare earth metals (La3+, Ce3+, Pr3+, Nd3+, Sm3+, Tb3+, Dy3+, and Y3+) and
compared their antibacterial activities [323]. The interaction of ciprofloxacincopper with nucleic acids and the determination of nucleic acids was carried
out by voltammetrically [324].
Chohan et al. (2005) reported the synthesis and antibacterial activity of
cobalt(II), copper(II), nickel(II) and zinc(II) complexes of ciprofloxacin
complexes [325]. Drevensek et al. (2005) prepared mixed-valence Cu(II)/Cu(I)
complex of ciprofloxacin by a hydrothermal reaction in presence of Lhistidine and compare the biological activities of various copper-ciprofloxacin
compounds [326]. El-Brashy et al. (2005) carried out the spectrophotometric
and atomic absorption spectroscopic determination of some fluoroquinolone
antibacterials by ion-pair complex formation with bismuth (III) tetraiodide
[327].
Han
et
al. (2005)
developed
a
simple,
rapid
and
sensitive
spectrofluorimetric method based on the formation of yttrium complexes for
the determination of norfloxacin [328]. Jimenez-Garrido et al. (2005)
prepared the coordination compounds of Cu(II) and Co(II) with ciprofloxacin
and enoxacin [329]. Sadeek (2005) studied the interactions of Mn(II), Co(II)
and Fe(III) with norfloxacin in acetone or methanol and the interpretation,
mathematical
analysis
and
evaluation
of
kinetic
parameters
of
thermogravimetric (TGA) and its differential (DTG), such as entropy of
activation, pre-exponential factors, activation energy evaluated by using
Department of Chemistry (SPU)
Chapter 1
32
Coats-Redfern and Horowitz-Metzger equations for two complexes were also
carried out [330]. Su et al. (2005) studied the interactions between
biomolecules
and
synthesized
lanthanide
complexes
(europium(III),
terbium(III)) and on the staining effect applied for tissue [331]. Xiao et al.
(2005) studied the reactions of the ciprofloxacin with metal salts (where
Metal = Mn, Co, Zn, Cd, and Mg) in the presence of aromatic polycarboxylate
ligands or under basic conditions [332]. Chen et al. (2006) reported an
unprecedented
1D
ladder-like
silver(I)
coordination
polymer
with
ciprofloxacin [333]. X-Ray crystallographic, NMR and antimicrobial activity
studies of magnesium complexes of racemic ofloxacin and its S-form,
levofloxacin was carried out by Drevensek et al. (2006) [334]. Drevensek et
al. (2006) reported the synthesis, characterization and DNA binding of
magnesium-ciprofloxacin (cfH) complex [Mg(cf)2].2.5H2O [335]. Efthimiadou
et al. (2006) synthesized the neutral and cationic mononuclear copper(II)
complexes with enrofloxacin and studied the interaction of the complexes
with
calf-thymus
DNA
with
diverse
spectroscopic
techniques
[336].
Efthimiadou et al. (2006) studied the crystal structure and biological
activities of the copper(II) complex with sparfloxacin [89]. Psomas et al.
(2006) synthesized and performed the biological activity of copper(II)
complexes with oxolinic acid [337]. Synthesis and spectroscopic study of
copper(II) and manganese(II) complexes with pipemidic acid was carried out
by Szymanska et al. (2006) [338]. Skrzypek et al. (2006) reported the
synthesis and spectroscopic studies of iron(III) complex with pipemidic acid
[339]. Yu et al. (2006) carried out the hydrothermal synthesis and reported
the
crystal
structure
and
antibacterial
activities
of
nickel(II)
and
manganese(II) complexes with ciprofloxacin [340].
Chattah et al. (2007) characterized the aluminium complexes of norfloxacin
and ciprofloxacin by NMR and IR spectroscopy [341]. Efthimiadou et al.
(2007) prepared, characterized and studied the bioactivity of metal
complexes of N-propyl-norfloxacin, pr-norfloxacin, with VO2+, Mn2+, Fe3+,
Co2+, Ni2+, Zn2+, MoO22+, Cd2+ and UO22+ [342]. Efthimiadou et al. (2007)
reported the antibacterial activity, and interaction with DNA of the vanadylenrofloxacin
complex
[343].
Mononuclear
copper(II)
complexes
with
quinolones and nitrogen-donor heterocyclic ligands were reported by
Efthimiadou et al. (2007) [344]. Efthimiadou et al. (2007) reported the
mononuclear metal complexes of pipemidic acid with VO2+, Mn2+, Fe3+, Co2+,
Department of Chemistry (SPU)
Chapter 1
33
Ni2+, Zn2+ and Cd2+ and studied the biological activities [345]. Efthimiadou et
al. (2007) reported the structure and biological properties of the copper(II)
complex with N-propyl-norfloxacin [346].
Solution studies on binary and ternary complexes of copper(II) with some
fluoroquinolones and 1,10-phenanthroline was carried out by Gameiro et al.
(2007) [347]. Imran et al. (2007) studied in vitro antibacterial activities of
ciprofloxacin-imines and their complexes with Cu(II), Ni(II), Co(II), and Zn(II)
[348]. Single crystal X-ray diffraction analysis was carried out to determine
the structure of polyoxovanadate complex of ciprofloxacin: V4O10([mu]2O)2[VO(H-Ciprof)2]2·13H2O by Liu et al. (2007) [349]. Obaleye et al. (2007)
studied the toxicological and antimicrobial properties of some iron(III)
complexes
of
experimental
ciprofloxacin
electron
[350].
density
Overgaard
of a
complex
et
al.
between
(2007)
studied
copper(II)
and
ciprofloxacin [351].
Pansuriya et al. (2007) synthesized and studied the biological aspects of
Fe(II), Fe(III) and Cu(II) complexes with ciprofloxacin [352-354]. Refat (2007)
carried out the synthesis and characterization of norfloxacin-Ag(I), Cu(II) and
Au(III) complexes and showed moderate activity against the gram positive
and gram negative bacteria as well as against fungi [355]. Ruiz et al. (2007)
synthesized several binary and ternary complexes of copper(II) with
norfloxacin and 1,10 phenantroline and also checked for nuclease like
activity [356]. Shaikh et al. (2007) synthesized the bismuth-norfloxacin
complex and evaluate the antimicrobial activity against Escherichia coli
(ATCC 25922), Klebsiella pneumoniae (NTCC 10320), Staphylococcus aureus
(ATCC 29213), Bacillus pumilis (NTCC 8241) and Staphylococcus epidermidis
(ATCC 12228) [357]. Shingnapurkar et al. (2007) prepared neutral dimeric
copper-sparfloxacin conjugate having butterfly motif with antiproliferative
effects against hormone [358]. Neutral mononuclear dioxomolybdenum(VI)
and dioxouranium(VI) complexes of oxolinic acid were prepareed by Tarushi
et
al.
(2007)
[359].
Investigation
of
interaction
of
fluoroquinolones
(ciprofloxacin, enrofloxacin, lomefloxacin, levofloxacin, ofloxacin, norfloxacin
and sparfloxacin) with aluminum, iron and magnesium ions using capillary
zone electrophoresis was carried out by Urbaniak et al. (2007) [360]. Xiao et
al. (2007) synthesized the complexes of Zn(II) [361]. Aristilde and Sposito
(2008) studied the molecular modeling of metal complexation (Ca2+, Mg2+,
Fe2+, Na+, and K+) by ciprofloxacin [90]. A europium complex of ciprofloxacin
Department of Chemistry (SPU)
Chapter 1
34
with formula [Eu(cfqH)(cfq)(H2O)4]Cl2.4.55H2O was prepared and its crystal
structure was investigated by Curman et al. [362]. Efthimiadou et al. (2008)
prepared
copper(II)
heterocyclic
complexes
ligands
with
sparfloxacin
(2,2'-bipyridine,
and
nitrogen-donor
1,10-phenanthroline
or
2,2'-
dipyridylamine) and also determined the structure-activity relationship
[363].
Mononuclear Mn2+, Fe3+, Co2+, Ni2+, Zn2+, Cd2+ complexes of enrofloxacin
were reported by Efthimiadou et al. (2008) [364]. In continuation of same
authors reported the structure, antimicrobial activity and DNA-binding
properties of the cobalt(II)-sparfloxacin complex [363]. Katsarou et al. (2008)
reported
the
copper(II)
complex
of
N-propyl-norfloxacin
and
1,10-
phenanthroline with antileukemic and DNA nuclease activities [365].
Liu et al. (2008) carried out synthesis, characterization, and DNA-binding
properties of Ln(III) complexes containing gatifloxacin and indicated that the
complexes and ligand bind to DNA via groove binding mode [366]. Pansuriya
and Patel (2008) prepared the Iron(III) and Cu(II) mixed ligand complexes
with ciprofloxacin and some neutral bidentate Schiff’s bases; and performed
the antibacterial activity and DNA-binding studies [367-368]. Psomas, G.
(2008) prepared the mononuclear metal complexes with ciprofloxacin where
(M= Mn2+, Fe3+, Co2+, Ni2+ and MoO22+) and evaluated DNA-binding properties
[369]. Psomas et al. (2008) reported the synthesis, characterization and
DNA-binding
of
the
mononuclear
dioxouranium(VI)
complex
with
ciprofloxacin [370]. Complexation equilibria of ciprofloxacin with proton and
metal ions in aqueous-organic mixtures were studied by Sekhon et al. (2008)
[371]. Turel et al. (2008) reported crystal structures and molecular modeling
calculations of ciprofloxacin and magnesium [372]. Crystal structure of
[Eu(cfqH)(cfq)(H2O)4]Cl2·4.55H2O was reported by Urman et al. (2008) [373].
Hydrothermal reactions of ciprofloxacin with Cu(ClO4)2·6H2O, and ofloxacin
with Cu(CH3COO)2·4H2O were carried out and the crystal structure,
antibacterial
activities
of
two
novel
[Cu(H-Cip)2]·(ClO4)2·6H2O
and
[Cu(Ofl)2·H2O]·2H2O were reported by Yu et al. (2008) [374]. Yuan et al.
(2008) studied the influence of Mg2+ and Cd2+ on the interaction between
sparfloxacin and calf thymus DNA [266]. The influence of Cu(II) ions on the
binding of pazufloxacin to calf thymus DNA (CTDNA) has been investigated
by Zhang et al. (2008) [375]. Zhao et al. (2008) studied on silver
Department of Chemistry (SPU)
Chapter 1
35
nanoparticles-sensitized fluorescence and second-order scattering of the
complexes of Tb(III) with ciprofloxacin and its applications [376].
The synthesis, antibacterial and anti-inflammatory activities of enoxacin
complexes
[M(eno)2(H2O)2]3H2O(M=Cu(II),
Ni(II)
or
Mn(II)
and
[M(eno)(H2O)2]Cl·4H2O (M=Fe(III) were studied by Arayne et al. (2009) [377].
Synthesis, structure and biological properties of several binary and ternary
complexes of copper(II) with ciprofloxacin and 1,10 phenanthroline were
reported by Hernández-Gil et al. (2009) [378]. A mixed copper complex with
deprotonated
nalidixic
acid
and
histamine
was
synthesized
and
characterized by Bivian-Castro et al. (2009) [379]. Patel et al. (2009) studied
DNA-interaction and in vitro antimicrobial studies of some mixed-ligand
complexes of cobalt(II) with ciprofloxacin and some neutral bidentate ligands
[380-381]. Skyrianou et al. (2009) reported the structure, cyclic voltammetry
and DNA-binding properties of the bis(pyridine)bis(sparfloxacinato)nickel(II)
complex [177]. Skyrianou et al. (2009) reported the Ni(II) mixed-ligand
complexes with the antibacterial drug sparfloxacin [178]. Tarushi et al.
(2009) reported the zinc mixed-ligand complexes of oxolinic acid and some
neutral bidentate ligands, and DNA-binding studies were also carried out
[382]. Tarushi et al. (2009) studied the structure and DNA-binding
properties of bis(quinolonato)bis(pyridine)zinc(II) complexes [383]. Urbaniak
and Kokot (2009) have focused on the factors that significantly influence the
stability of fluoroquinolone-metal complexes [384]. Vieira et al. (2009) have
studied the synthesis and antitubercular activity of palladium and platinum
complexes with fluoroquinolones (ciprofloxacin, levofloxacin, ofloxacin,
sparfloxacin, and gatifloxacin) [385-386]. Complexes of sparfloxacin with
Fe3+, VO2+, Mn2+, Ni2+ and UO22+ were synthesized and biological evaluation
was carried out by Efthimiadou et al. (2010) [387]. Antibacterial and DNA
interaction of zinc(II) complexes ciprofloxacinand some neutral bidentate
were studied by Patel et al. (2010) [388]. Patel et al. (2010) prepared square
pyramidal copper(II) complexes with fourth generation fluoroquinolone and
neutral bidentate ligands. Antibacterial, SOD mimic and DNA-interaction
studies were also carried out [389]. Skyrianou et al. (2010) reported the
interaction of nickel(II) with the antibacterial drug oxolinic acid [179].
Department of Chemistry (SPU)
Chapter 1
36
1.9 Present work
The research work described in this thesis is in connection with the
synthesis, spectroscopic, thermal, magnetic studies of Ni(II), Cd(II) and
VO(IV) mixed-ligand complexes with ciprofloxacin and bidentate ligands. The
biocidal activity of the ligands, metal salts and their complexes have been
tested against microbial cultures. The DNA binding activities has been
performed using absorption titration, viscometry and gel electrophoresis
techniques. The results of these investigations are presented in following
chapters.
Chapter-2 contains the synthesis and characterization of the neutral
bidentate ligands.
Chapter-3 is divided into two parts. First part, deals with synthesis of Ni(II),
Cd(II) and VO(IV) complexes.
General reaction schemes for synthesis of coordination compounds of Ni(II),
Cd(II) and VO(IV) are as follow:
Ni(NO3)2·6H2O + Cpf.HCl + An → [Ni2(Cip.)2(An)2(pip)(H2O)2]·2H2O
Cd(OAc)2·H2O + Cpf.HCl + An → [Cd2(Cip.)2(An)2(pip)(H2O)2]·2H2O
VOSO4·3H2O + Cpf.HCl + Ln → [VO(Cpf.)( Ln)]·2H2O
where,
Cpf.HCl
=
ciprofloxacin
hydrochloride,
Cip.H
=
cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic
7-chloro-1-
acid,
pip
=
piperazine, An = A1- A18 neutral bidentate ligands and Ln = L1-L9 uninegative
bidentate ligands.
Second part deals with characterization of monomeric and dimeric
complexes. The complexes have been characterized using elemental analysis,
IR spectra, mass spectra, reflectance and UV-Vis. spectroscopy, magnetic
measurements, and thermogravimetry analyses.
Chapter-4
contains
Minimum
Inhibitory
Concentration
(antimicrobial
activity) of the compounds. MIC have been assayed against three Gram(-ve) i.e.
E. coli and P. aeruginosa, S. marcescens and two Gram(+ve) i.e. S. aureus, B.
subtilis microorganisms using the doubling dilution technique.
Department of Chemistry (SPU)
Chapter 1
37
Chapter-5 deals with DNA binding study of mixed-ligand complexes by
absorption titration technique and the binding constants Kb are calculated
for each prepared complex.
Chapter-6 deals with viscosity measurements of Herring Sperm DNA with
the prepared complexes.
Chapter-7 deals with DNA cleavage activity of compound towards pUC19
DNA. Gel electrophoresis technique has been utilized for this study. All the
coordination compounds show higher nuclease activity compare to parental
ligands and metal salts.
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Department of Chemistry (SPU)