DNA interaction studies of rhenium compounds with Schiff base chelates encompassing biologically relevant moieties

Article abstract of DOI:10.1080/15257770.2019.1639058

Herein, we report the DNA interaction studies of rhenium(I) and -(V) compounds with Schiff base chelates encompassing biologically relevant moieties. More specifically, the DNA interaction capabilities of these rhenium complexes were probed using Gel Elec

Full text of DOI:10.1080/15257770.2019.1639058

Nucleosides, Nucleotides and Nucleic Acids
ISSN: 1525-7770 (Print) 1532-2335 (Online) Journal homepage: https://www.tandfonline.com/loi/lncn20
DNA interaction studies of rhenium compounds
with Schiff base chelates encompassing
biologically relevant moieties
Muhammed Bilaal Ismail, Irvin Noel Booysen & Matthew Piers Akerman
To cite this article: Muhammed Bilaal Ismail, Irvin Noel Booysen & Matthew Piers
Akerman (2019): DNA interaction studies of rhenium compounds with Schiff base chelates
encompassing biologically relevant moieties, Nucleosides, Nucleotides and Nucleic Acids, DOI:
10.1080/15257770.2019.1639058
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NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
https://doi.org/10.1080/15257770.2019.1639058
DNA interaction studies of rhenium compounds with
Schiff base chelates encompassing biologically
relevant moieties
Muhammed Bilaal Ismail, Irvin Noel Booysen, and Matthew Piers Akerman
School of Chemistry and Physics, University of KwaZulu-Natal, Pietermaritzburg, South Africa
ABSTRACT
ARTICLE HISTORY
Received 17 January 2018
Accepted 29 June 2019
Herein, we report the DNA interaction studies of rhenium(I)
and -(V) compounds with Schiff base chelates encompassing
biologically relevant moieties. More specifically, the DNA inter-
action capabilities of these rhenium complexes were probed
using Gel Electrophoresis and Calf Thymus–DNA titrations
monitored by temperature-controlled electronic spectroscopy.
The DNA binding modes of the metal compounds were corro-
borated by molecular docking simulations. In addition, the
synthesis and characterization of a novel facial tricarbonyl
rhenium(I) compound, fac-[Re(chrs)(CO)3Br], (chrs ¼ {3-{[(2-
hydroxyphenyl)imino]methyl}-4H-chromen-4-one) are reported.
KEYWORDS
DNA interaction; gel
electrophoresis; molecular
docking; rhenium;
Schiff base
Introduction
The interaction of transition metal complexes towards DNA is a central
scientific focus due to its relevance in cancer research and molecular biol-
ogy.[1,2] Metal ions and their complexes can interact with DNA covalently
and/or non-covalently; therefore, an understanding on their binding modes
is particularly important for the design of modern metallopharmaceuti-
cals.[3] Covalent bonding of a metal complex to the DNA double helix is
typically initiated by substitution of a labile co-ligand within the coordin-
ation sphere of the metal complex followed by coordination of the metal
centre to a nitrogen donor of a DNA nucleotide base. Non-covalent inter-
ꢀ
calative interactions are found in the form of p!p stacking between the
pi-conjugated chromophores of metal complexes and DNA nucleotide
bases.[4] In addition, non-covalent groove-binding occurs via van der
Waals and hydrogen- or hydrophobic-interactions along the major or
minor groove of the DNA double helix. Lastly, electrostatic interactions
can be induced by columbic forces between a metal complex and the nega-
tively-charged phosphate backbone of DNA.[4–6]
CONTACT Irvin Noel Booysen
Booyseni@ukzn.ac.za
School of Chemistry and Physics, University of
KwaZulu-Natal, Private Bag X01, Scottsville, Pietermaritzburg, 3209, South Africa.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lfnn.
Supplemental data for this article is available online at https://doi.org/10.1080/15257770.2019.1639058.
ß 2019 Taylor & Francis Group, LLC

2
M. B. ISMAIL ET AL.
Rhenium exhibits diverse coordination chemistry and its organometallic
complexes have been utilized in myriad medicinal applications.[7–10] In par-
ticular, the b-emitting 186- and 188-rhenium radionuclides have optimal
half-lives and energies which are ideally suited for the development of
therapeutic radiopharmaceuticals.[11] However, the pharmacological effica-
cies of rhenium radiopharmaceuticals are typically poor, which is largely
attributed to their lack of target-specificity. To address this concern, radio-
labelling of multidentate chelators encompassing various biologically active
moieties can be conducted.[12–14] Subsequently, the bio-active groups of
these next-generation rhenium radiopharmaceuticals could facilitate well-
defined biodistribution patterns and facile interaction with mutated DNA
(i.e. malignant growths) at the target sites.[14]
In comparison with other metals, DNA interaction studies of rhenium
compounds have not been widely reported and to the best of our know-
ledge, these research findings represent one of few studies reported on the
interactions between rhenium(V) complexes and calf-thymus (CT)–DNA.
In addition, gel-electrophoresis studies were conducting using CT–DNA
with the individual rhenium(I) and -(V) Schiff base compounds containing
nucleotide bases, benz(imidazole/othiazole) or chromone moieties: trans-
[Re(ddd)(Hduo)(PPh3)2]I (1) (H2ddd ¼ 5,6-diamino-1,3-dimethyl uracil
and H3duo ¼ [N-(2-hydroxybenzylidene)-5-amino-1,3-dimethyl uracil]);
fac-[Re(CO)3Br(adp)] (2) (adp ¼ {5-amino-1,3-dimethyl-6-[(Z)-(pyridin-2-
ylmethylidene)amino]pyrimidine-2,4(1H,3H)-dione}); fac-[Re(CO)3Br(aap)]
(3) (aap ¼ {4-[(Z)-(2-aminobenzylidene)amino]pyrimidin-2(1H)-one}); cis-
[Re(bcp)OCl2(PPh3)] (4) (Hbcp ¼ [N-(2-hydroxybenzylidene)-benzothia-
zole]) (l-bzp)2[Re(CO)3]2; (5) (Hbzp ¼ [N-(2-hydroxybenzylidene)-benzi-
midazole]); fac-[Re(CO)3(bzch)Cl] (6) (bzch ¼ (2-benzimidazole-4H-
chromen-4-one)); fac-[Re(CO)3(bsch)Cl] (7) (bsch ¼ 2-benzothiazole-4H-
chromen-4-one); [ReO(Hns)] (8) (Hns ¼ bis-[(2-phenylthiolate)imino-
methyl]-methyl-1-(2-hydroxyphenyl)prop-2-en-1-one) and [ReO(OCH3)
(PPh3)(Huch-OCH3)] (9) (H2uch ¼ [5-(6-amino-1,3-dimethyluracil)imino-
methyl-4H-chromen-4-one]).[15]
This research studies serves as an evolution of our recent reports,
whereby the rhenium compounds listed above have been previously
reported and now have their DNA interaction capabilities investigated by
UV–Vis titrations, gel-electrophoresis and molecular docking studies.
Furthermore, the facial tricarbonyl rhenium(I) compound, fac-
[Re(chrs)(CO)3Br] (10), (chrs ¼ {3-{[(2-hydroxyphenyl)imino]methyl}-4H-
chromen-4-one}, see Figure 1) has not been previously reported and hence
in addition to its DNA interaction studies, its synthesis, characterization
and crystal data are included. Moreover, this investigation provides a com-
prehensive understanding with respect to the DNA binding capabilities of

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
3
O
N
OH
O
Figure 1. Structure of chrs.
the rhenium compounds 1–9 and provides impetus to explore their in vitro
cytotoxicity and applied radiochemistry. Of particular significance is how
the diverse coordination environments of the respective rhenium(I) and
-(V) centres, as well as the varying stereo-electronic properties of the differ-
ent bio-relevant chelators, dictated the DNA interaction modes of the cor-
responding metal complexes.
2. Experimental
2.1. Materials and methods
Ammonium perrhenate, rhenium pentacarbonyl bromide, rhenium
pentacarbonyl chloride triphenylphosphine, hydrochloric acid, hydrobromic
acid, hydroiodic acid, 3-formylchromone, 5,6-diamino-1,3-dimethyluracil,
2-aminobenz(othiazole/imidazole), cytosine, salicylaldehyde, 2-aminobenzal-
dehyde, picolinaldehyde, 1,2-diaminobenzene, 2-aminophenol, 2-aminothio-
phenol, trifluoroacetic acid, phosphate-buffered saline (PBS) tablets and calf
thymus (CT)–DNA were obtained from Sigma Aldrich. The
oxorhenium(V) precursors were synthesized as described by literature
methods.[16] DNA chips, DNA 1 K gel and stain, DNA ladder and loading
buffer were all obtained within a DNA 1 K Analysis Kit from Bio-Rad. All
solvents were obtained from Merck SA. These chemicals were used without
any further purification. The infrared spectra were recorded on a
1
Perkin–Elmer Spectrum 100 from 4000 to 650 cmꢁ1. H NMR spectra were
obtained using a Bruker Avance 400 MHz spectrometer. All NMR spectra
were recorded in DMSO-d6. UV–Vis spectra were recorded using a
Perkin–Elmer Lambda 25. Melting points were determined using a Stuart
SMP3 melting point apparatus. The conductivity measurements were deter-
mined at 295 K on a Radiometer R21M127 CDM 230 conductivity and pH
meter. Toluene was dried with sodium wire and stored in the presence of
dry 4 Å microsieves. The redox properties of the metal complexes were
investigated by cyclic and square wave voltammetry. The concentration of
the metal complexes was 2 mM and tetrabutylammoniumtetrafluoroborate
(0.1 M) was used as the supporting electrolyte. A Metrohm Autolab
Potentiometer was used for measurements equipped with a three-electrode

4
M. B. ISMAIL ET AL.
system: pseudo AgjAgCl reference electrode, a glassy carbon working elec-
trode and Pt auxiliary counter electrode.
2.2. Synthesis of 3-{[(2-hydroxyphenyl)imino]methyl}-4H-chromen-4-
one (chrs)
Equimolar amounts of 2-aminophenol (157 mg; 1.44 mmol) and 3-formyl-
chromone (250 mg; 1.44 mmol) were added to 20 cm3 of methanol and
heated until reflux for 3 hours. A large quantity of brown precipitate was
filtered, washed with 3 ꢂ 2 cm3 of cold methanol and 2 ꢂ 3 cm3 of petrol-
eum ether and left to dry in desiccator. Yield: 92%. M.P: 202.4–205.8 ꢃC. IR
1
(ꢀmax/cmꢁ1): v(O–H) 3160 w, v(C ¼ O) 1639 s, v(C ¼ N) 1549 s. H NMR
(303 K ppm–1): 10.29 (br s, 1 H, OH), 8.16 (d, 1 H, H8), 7.86 (d, 1 H, H11),
7.58–7.44 (m, 2 H, H9, H10), 7.09–7.18 (m, 2 H, H4, H5), 6.99–6.92 (m,
2 H, H1, H2), 6.87 (t, 1 H, H3), 5.84 (s, 1 H, H6). UV–Vis (MeOH, kmax (e,
Mꢁ1 cmꢁ1)): 243 nm (6505), 268 nm (5692), 312 nm (2434),
404 nm (17280).
2.3. Synthesis of fac-[Re(chrs)(CO)3Br] (10)
The ligand chrs (65.3 mg, 246 mmol) was added to [Re(CO)5Br] (100 mg,
246 mmol) in 20 cm3 of dry toluene. The resultant mixture was heated at
reflux temperature under an inert N2 atmosphere for 4 hours. A dark green
precipitate was filtered and dried overnight in a desiccator. This precipitate
was dissolved in dichloromethane and layered with n-hexane from which
yellow parallelogram-shaped crystals grew after five days. Yield: 72%. M.P:
286.4–289.2 ꢃC. IR (ꢀmax/cmꢁ1): v(O–H) 3318 w, v(CꢄO)fac 2020 and
1
1878 s, v(C ¼ O) 1632 m, v(C ¼ N) 1557 m. H NMR (303 K ppm–1): 9.95
(br s, 1 H, OH), 9.42 (s, 1 H, H1), 8.56 (s, 1 H, H6), 8.32 (d, 1 H, H8), 8.14
(t, 1 H, H9), 8.01 (d, 1 H, H11), 7.69 (t, 1 H, H10), 7.28 (d, 1 H, H5), 7.13
(t, 1 H, H4), 7.00 (d, 1 H, H2), 6.89 (t, 1 H, H3). UV–Vis (DMF, kmax (e,
Mꢁ1 cmꢁ1)): 242 nm (17248), 260 nm (14836), 284 nm (16824), 320 nm
(12429),
395
(12042).
Conductivity
(DMF,
10ꢁ3
M)
¼
8.64 Xꢁ1 cmꢁ2 molꢁ1.
2.4. X-ray crystallography
The X-ray data for the metal complex 10 was recorded on a Bruker Apex
Duo equipped with an Oxford Instruments Cryojet operating at 100 K and
an Incoatec microsource operating at 30 W power. Crystal and structure
refinement data are given in Table 1 and selected bond lengths and angles
for 10 are given in Table 2. The data were collected with Mo Ka
(k ¼ 0.71073 Å) radiation at a crystal-to-detector distance of 50 mm.

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
5
Table 1. Crystal data and structure refinement data for compound 10.
Chemical formula
C19H11NO6ReBr
Formula weight
Temperature (K)
Crystal system
Space group
615.40
100
Monoclinic
P21/n
a ¼ 7.4735(4)
b ¼ 14.4084(7)
c ¼ 16.4626(7)
b ¼ 96.997(3)
1759.51(15)
4
ꢀ
ꢃ
Unit cell dimensions (Å,
)
V (Å3)
Z
Density (calc.) (Mg m–3
)
2.32
9.22
Absorption coefficient (mm–1
)
F(000)
1160
1.9-26.4
h range for data collection (ꢃ)
Index ranges
ꢁ8/6; -18/17; -20/20
Reflections measured
Observed data [I > 2r(I)]
Data/restraints/parameters
Goodness of fit on F2
R, wR2
14593
2947
3339/0/256
1.050
0.0200, 0.042
Table 2. Selected bond lengths [Å] and bond angles [ꢃ] for 10.
Re–C18
1.912(4)
C20–Re–O2
173.5(1)
Re–C19
Re–C20
Re–Br
Re–O2
Re–N
1.908(3)
1.915(4)
2.6327(5)
2.136(2)
2.186(3)
178.4(1)
C19–Re–Br
O2–Re–N
C13–O6
C19–O4
C8–O2
174.2(1)
84.2(1)
1.361(5)
1.151(5)
1.257(4)
C18–Re–N
The following conditions were used for the Bruker data collection: omega
and phi scans with exposures taken at 30 W X-ray power and 0.50ꢃ frame
widths using APEX2.[17]. The data were reduced with the program
SAINT[17] using outlier rejection, scan speed scaling, as well as standard
Lorentz and polarization correction factors. A SADABS[17] semi-empirical
multi-scan absorption correction was applied to the data.[18] Direct meth-
ods, SHELXS-97[19] and WinGX[20] were used to solve the structure. All
non-hydrogen atoms were located in the difference density map and
refined anisotropically with SHELXL-97.[19] All hydrogen atoms were
included as idealized contributors in the least squares process. Their posi-
tions were calculated using a standard riding model with C–Haromatic dis-
tances of 0.93 Å and Uiso ¼ 1.2 Ueq.
2.5. UV–Vis DNA binding titrations
CT–DNA was prepared in PBS at a pH of 7.2 and the DNA binding stud-
ies of the metal complexes were carried out in MeOH. The DNA solution
afforded a ratio of UV absorbance at 260 and 280 nm of approximately
1.9:1 which indicates that the DNA was sufficiently free of protein.[21]

6
M. B. ISMAIL ET AL.
In addition, the CT–DNA concentration per nucleotide was determined
by UV absorption spectroscopy using the molar absorption coefficient
(e260¼6600 Mꢁ1 cmꢁ1).[21] The resultant stock DNA solution was stored at
a temperature of 4 ꢃC and used within 2 days after preparation.
Furthermore, the respective metal complexes and CT–DNA solutions were
incubated for 24 hours at 25 ꢃC prior to any UV–Vis measurements.[22]
The UV–Vis spectra were attained for a solution of metal complex (of
known concentration in methanol) with varying nucleotide concentrations
(0–200 lM) in PBS. The data attained from the absorption titration experi-
ments were fitted to the following equation to obtain the intrinsic binding
constant (Kb):
½
ꢅ
½
ꢅ
DNA
DNA
1
¼
þ
:
e ꢁ e
e ꢁ e
b
K e ꢁ e
ð
fÞ
ð
fÞ
bð
fÞ
a
b
In this equation, [DNA] is the concentration of DNA in base pairs, ea is
the extinction coefficient of the observed absorption band at the given
DNA concentration (corresponds to Aobs/[complex]), ef is the extinction
coefficient of the complex free in solution, and eb is the extinction coeffi-
cient of the complex when fully bound to DNA. A plot of [DNA]/[ea – ef]
versus [DNA] gave a slope 1/[ea – ef] and Y intercept equal to 1/
Kb[eb – ef]. The intrinsic binding constant (Kb) is estimated to be the ratio
of the slope to the intercept.[22]
2.6. Gel electrophoresis
A Bio-Rad ExperionTM Automated Electrophoresis System was used to per-
form the CT gel electrophoresis study using the reagents and supplies from
a Bio-Rad DNA 1 K kit. The system consists of the ExperionTM electro-
phoresis, priming and vortex station. CT–DNA (2 mM, prepared in the
same manner as for the DNA binding titrations) and the metal complexes
(at different concentrations) were incubated at room temperature, 24 hours
prior to analysis.
2.7. Computational studies
Computational calculations were conducted with GAUSSIAN 09W.[23]
Geometry optimizations of the metal complexes were achieved through
DFT calculations using the B3LYP functional, with an accompanying
hybrid basis set viz. the 6-311Gþþ (d, p) basis set was applied to all the
nonmetal atoms and the LANL2DZ basis set, which makes use of effective
core potentials, applied to the metal centre.[24,25] The use of these computa-
tional settings was validated by the reasonable agreement between the

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
7
optimized and geometrical parameters. The minor deviations are attributed
to the fact that gas phase optimized structures do not account for nonclass-
ical hydrogen bonding interactions or any short distance contacts.
Furthermore, the lack of any negative Eigen values in the frequency calcu-
lations confirmed that the optimized structures are at a global minima on
the potential energy surfaces.[26] Molecular docking simulations were car-
ried out using the optimized structures and the programme Patchdock Beta
version 1.3. Molecular interactions were refined using Firedock[27] and vis-
ualizations were adapted through YASARA View.[28] The B–DNA structure
(LOX) (PDB ID: 1F8N) was obtained from the Protein Data Bank and all
water molecules were removed prior to the docking procedure.
3. Results and discussion
3.1. Synthesis and characterization of fac-[Re(chrs)(CO)3Br] (10)
The equimolar coordination reaction between chrs and [Re(CO)5Br]
afforded an octahedral rhenium(I) complex, fac-[ReI(CO)3Br(chrs)]. In con-
trast to the intra-ligand cyclization observed for the Hbcp and Hbzp chro-
mone Schiff bases in the formation of 5 and 6, the chrs chelator of 10
remained intact and coordinated as a neutral bidentate chelator via its
N
iminoOketonic donor set. The compound is soluble in an array polar sol-
vents such as alcohols, water, chlorinated and high-boiling point aprotic
solvents. In addition, a low-molar conductivity value is observed due to
this metal complex’s charge neutrality.
The proton NMR spectrum of 10 shows well-resolved signals, which
emphasizes the diamagnetic nature of the d6 metal centre and are compar-
able to analogous signals found in the proton NMR spectrum of its free-lig-
and. In particular, broad OH singlets found at 8.16 and 9.95 ppm for ligand
chrs and 10 (Figure S1) respectively, confirm that no cyclization of chrs
took place upon coordination. Similarly, the shift of Schiff base singlet
(found within a multiplet for chrs at 6.92–6.99 ppm) in comparison to 10
(9.42 ppm) is indicative of rhenium(I) coordination through the Nimino
atom which further infers that no cyclization took place. The IR spectra for
10 are dominated by intense bands of the facial tricarbonyl co-ligands
between 2020 and 1878 cmꢁ1. All the other bands associated with the chro-
mone and heterocyclic moieties of 10 are found at medium intensity
between 1639 and 1557 cmꢁ1 (Figure S2).
In the UV–Vis spectrum, three absorbance maxima observed between 0
ꢀ
and 350 nm for 10 are ascribed to intraligand p–p transitions whereas the
electronic transition at 395 nm is ascribed to a ligand-to-metal charge
transfer band. For 10, (Figure S3) the diffusion controlled processes at
Epa¼0.02 and Epc¼–0.87 V are best described as a ligand induced oxidation

8
M. B. ISMAIL ET AL.
Figure 2. An ORTEP view of compound 10 showing 50% probability displacement ellipsoids
and the atom labeling.
and reduction respectively, see Figure S4. The redox process at –1.12 V is
tentatively attributed to a Re(I/0) reduction which falls within range for
that of other tricarbonyl rhenium(I) compounds (–0.98 to –1.26 V versus
AgjAgCl) and an irreversible Re(I/II) oxidation process is observed
at 0.80 V.[29]
3.2. Crystal structure of fac-[Re(CO)3(chrs)Br] (10)
Compound 10 crystallizes out as a monomeric, neutral compound, see
Figure 2. Four molecules of 10 occupy an asymmetric unit cell with a
P21/n space group. The Re–CO [1.906(3)–1.915(4) Å] and Re–Br
[2.6327(5) Å] bonds within the coordination sphere are typical of
facial
tricarbonylrhenium(I)
compounds,
e.g.
fac-[Re(CO)3Br[(2-
pyridylmethyl)NH2]], fac-[Re(CO)3[(2-pyridylmethyl)2NH]]Br and their
derivatives [Re–CO: 1.904(6)–1.927(4) Å, Re–Br: 2.618(1)–2.6462(7) Å].[30]
The Re–Oketonic bond length of 2.136(2) Å compares well with that of 7
[2.147(2) Å][15] while the Re–Nimino [2.186(3) Å] bond distance is within
range found for other rhenium(I) Schiff base compounds
[2.144(4)–2.194(5) Å].[31] Furthermore, the constrained O2–Re–N bite
angle [84.2(1)ꢃ] induces non-linearity of the equatorial [C18–Re–N:
178.4(1)ꢃ and C20–Re–O2: 173.5(1)ꢃ] and axial [C19–Re–Br: 174.2(1)ꢃ]
bond angles.
The deviation of the latter is further influenced by classical intramolecu-
lar hydrogen bonding [O6–HꢆꢆꢆBr ¼ 2.5508(4) Å]. In addition, this hydro-
gen-bonding allows the chromone and phenol planes to lie almost perfectly
perpendicular to each other (88.47ꢃ). Hybridization of the C–O bonds are
clearly depicted when comparing the C13–O6 single bond length
[1.361(5) Å] to the double bond C8–O2 [1.257(4) Å] and the carbonyl tri-
ple bond C19–O4 [1.151(5) Å]. In addition, the molecules pack along the

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
9
Figure 3. The overlay UV–Vis absorption spectra of compound 1. The dashed line indicates
complex 1 free of any DNA and the hypochromic effect (indicated by the arrow) is due to pro-
gressive increments of a 2 mM CT–DNA solution.
[b]-axis due to short contacts between adjacent phenol moieties
[3.156(5)–3.382(4) Å] and adjacent CimineꢆꢆꢆO3 atoms [3.079(4) Å] of neigh-
bouring molecules.
3.3. DNA interaction studies of pyrimidine Schiff base rhenium
compounds 1–3
Gradual electronic spectral changes upon the addition of increasing
amounts of DNA is one of the most common methods used to determine
the binding mode and extent of the interaction between inorganic or
organic compounds with DNA. Upon the addition of CT–DNA, the
absorption intensity of a metal complex may increase (hyperchromism),
decrease (hypochromism) or cause a red-shift in absorption wavelength of
a selected peak maximum (bathochromism). In general, hypochromism
accompanied with bathochromism is associated with an intercalative bind-
ing mode of metal complexes in the DNA helix and involves a strong
ꢀ
p!p stacking interaction between aromatic chromophores and the base
pairs of DNA.[32,33] The DNA titration spectra for 1, 2 and 3 are similar in
that they each display hypochromism (between 15 and 20%) with zero or
negligible bathochromic effects (1: 0%, 2: 0%, 3: 0.3%), see Figures 3, 4 and
S5. The data were consistent for compounds of a DNA groove-binding
nature e.g. the groove-binding metal complex, fac-[Re(CO)3(phendione)Cl]
{phendione ¼ 1,10-phenanthroline-5,6-dione} which exhibits hypochrom-
ism (albeit 30%) and a negligible shift in absorption maximum wave-
length.[22] In addition, the binding constants (Kb values) were calculated
using the linear plot insets of [DNA]/[eaꢁef] versus [DNA]. Kb was found

10
M. B. ISMAIL ET AL.
Figure 4. The overlay UV–Vis absorption spectra of compound 2. The dashed line indicates
complex 2 free of any DNA and the hypochromic effect (indicated by the arrow) is due to pro-
gressive increments of a 2 mM CT–DNA solution.
to be 1.01 ( 0.42)ꢂ03 Mꢁ1, 1.17 ( 0.32)ꢂ103 Mꢁ1 and 2.75 (
0.78)ꢂ105 Mꢁ1 for 1, 2 and 3, respectively. This compares well with litera-
ture metal complexes containing multidentate Schiff base ligands
(103 Mꢁ1>Kb>106 Mꢁ1).[34–37]
Molecular docking is a well-established computational technique for pre-
dicting the best interaction between a metal complex and DNA to form a
new DNA–metal complex conjugate of lowest possible energy.[38] Relatively
smaller molecules tend to interact with the DNA minor groove due to
minute steric interferences and generally the lowest energy metal
complex–DNA adducts arises from metal complexes with freely rotational
aromatic rings. Furthermore, these metal complexes can orientate to the
curvature of the groove while displacing water molecules.[39] Molecular dock-
ing simulations conducted on 1–3 corroborated their experimental CT–DNA
binding modes where computationally, all three metal complexes exhibit
groove binding: 1 docks within the major groove of B–DNA (nucleotide
base pairs: AT, AT, TA, TA, CG) and the other two metal compounds dock
within the minor groove (nucleotide base pairs: GC, CG, GC). These metal
compounds have lowest calculated global energies of –39.48, –47.65 and
–40.03kJ molꢁ1, respectively (Figures 5, S6 and S7). The adducts of 2 and 3
with B–DNA are largely stabilized by hydrogen bonding: between the brom-
ide co-ligand and guanine amine for 2 and the axial tricarbonyl co-ligand
and a phosphate oxygen atom for 3. This affords similarity between the con-
figurations of the rhenium(I) compounds 2 and 3, where both Schiff base
chelators interact with the hydrophobic B–DNA interior and their more
polar tricarbonyl moieties with the hydrophilic phosphate backbone.
As expected, compound 1 has a larger calculated van der Waals radius
(8.798 Å) from its geometric centre in comparison to 2 and 3 (radii of

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
11
Figure 5. Docked position of 3 bound to the minor groove of B–DNA: ball and stick view (left)
and DNA molecular surface view (right).
equal size, 7.037 Å) with steric hindrance of the bulky PPh3 group rational-
izing its affinity for the major groove of B–DNA instead of the minor
groove. However, literature trends reveals that metal complexes with triphe-
nylphosphines within their coordination spheres can bind within either
the major or minor grooves of B–DNA, like in the case of the series of
silver(I) complexes: [AgCl(PPh3)2(MTZD)], {[AgCl(PPh3)2(MBZT)] and
[AgCl(PPh3)2(CMBZT)] (where MTZD ¼ 2-mercaptothiazolidine, MBZT
¼ 2-mercaptobenzothiazole and CMBZT ¼ 5-chloro-2-mercaptobenzothia-
zole).[40] Further observation of the complex–DNA adduct of 1 reveals
three firm intermolecular hydrogen bonds, arising from the uracil moiety
of Hduo, stabilizes the DNA adduct of 1 and B–DNA in the major groove
including the methyl carbons with thymine Oketone atom (2.356 Å) and
guanine ring nitrogen (2.207 Å) as well as Oketone with adenine
Namine (2.012 Å).
Interestingly, even though the docked structures of 1 and 2 exhibit only
a slightly lower energy than 3, metal complexes 1 and 2 display a substan-
tially lower experimental intrinsic binding constant (Kb) value. This would
suggest that there is a combination of experimental factors for 1 and 2 to
overcome to be able to dock in energetically favourable positions.
Evaluating the structure of the Schiff base chelators for 1 and 2, the uracil
moieties each contain two polar ketone and two non-polar methyl groups.
Thus, in order for the chelating moieties to facilitate groove-binding, the
competitive polarity interactions must breach analogous interactions found
within the interior and exterior of the CT–DNA double helix.

12
M. B. ISMAIL ET AL.
Figure 6. Lane L: DNA Ladder of known base pair lengths, Lane 1: CT DNA only, Lane 2: DNA
þ 10 mM of 1, Lane 3: DNA þ 50 mM of 1, Lane 4: DNA þ 100 mM of 1; Lane 5: DNA þ 10 mM
of 2, Lane 6: DNA þ 50 mM of 2, Lane 7: DNA þ 100 mM of 2; Lane 8: DNA þ 10 mM of 3,
Lane 9: DNA þ 50 mM of 3 and Lane 10: DNA þ 100 mM of 3.
A gel electrophoresis study was conducted to evaluate whether the
groove-binding metal complexes induce DNA cleavage, see Figure 6. In
comparison with CT–DNA only (Lane 1), it is seen that the cleaving ability
of all three metal compounds correlate with increasing compound concen-
tration. At the highest concentrations (Lanes 4, 7 and 10) compounds 1
and 3 display a similar activity, greater than that of 2. This suggests that 1
and 3 are able to produce more DNA damaging reactive oxygen species
than that of 2. DNA fragments greater than 1500 bp are observed for 1–3
as CT–DNA contains DNA chains far greater in length than the limit of
detection in this study.[41]
3.4. DNA interaction studies of benz(imidazole/othiazole) rhenium
compounds 4–6
The overlay electronic spectra of 4–6 indicate no significant structural con-
tusions as implied by the lack of red or blue shifts of peak maxima upon
DNA addition (4: 0 nm, 5: 3 nm bathochromism, 6: 0 nm), see Figures
S8–S10. However, compound 4 displays a substantial hyperchromic shift
(ꢇ20%) of the peak at 262 nm which is evidence for the formation of an
adduct between this compound and the double-helical DNA.[42] This type
of shift is further consistent for a metal complex of groove-binding nature,

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
13
as illustrated by cobalt(II) and nickel(II) complexes of salicylaldehyde 2-
phenylquinoline-4-carboylhydrazone (H2L) {[M(HL)(H2O)3](NO3)2 where
M ¼ Co or Ni}.[43] Compounds 5 and 6 are similar in that they display
hypochromic effects, perhaps as a result from the contraction of DNA
phosphate chains.[44,45]. Although 5 exhibits both properties of an interca-
lative complex, the minor observed red-shift coupled with the large dinu-
clear structure of 5 make this mode of interaction unlikely. Thus
compounds 4–6 are designated as groove-binding compounds and
exhibit binding constants {4: Kb¼2.76 ( 0.94)ꢂ105 Mꢁ1, 5: Kb¼4.32
( 0.62)ꢂ103 Mꢁ1 and 6: Kb¼9.37 ( 0.55)ꢂ104 Mꢁ1} which are compar-
able with other such metal compounds found in literature (Kb:
5.60 ꢂ 103–8.72 ꢂ 107 Mꢁ1).[46,47]
Molecular docking studies of 4–6 show that all three metal compounds
bind to the minor groove of B–DNA in the GC, CG, GC, CG region
(Figures S11–S13). Compound 5 displays the highest global energy of the
three compounds (4: –35.06, 5: –28.14 and 6: –47.38 kJ molꢁ1) primarily
due to its large dinuclear structure (van der Waals radius ¼ 8.078 Å).
Flexibility of molecules plays an important role in increasing
molecule–DNA stability as they can orient more easily along the minor
groove.[48,49] The rigidity of 5 may prevent manoeuvrability within the
B–DNA minor groove and could further attest for its lower intrinsic bind-
ing constant. Compound 6 displays two strong bonding interactions:
between its chlorine co-ligand and an outer Ophosphate atom (2.300 Å) as
well as a chromone carbon and guanine Namine atom (2.533 Å). This bond-
ing pattern results in 6 having the lowest energy of the three compounds.
Compound 5 also exhibits two close contacts: a triphenylphosphine carbon
atom with a guanosine ribose carbon atom (2.694 Å) and chlorine co-ligand
with a ribose methyl moiety (2.616 Å). Despite the difference in global
energies, compounds 4 and 6 display a similar calculated binding constant
which suggests that there are dynamic factors for 6 to overcome to be able
to dock in its energetically favourable position.[50]
It is common for transition metals to cleave DNA via metal-mediated
radical production.[51] Compounds 4–6 were incubated with CT–DNA to
preliminary assess if the groove-binding compounds are able to cleave
DNA in this manner, which can further provide insight about their
potential cytotoxicities.[52] From the virtual gel stain (Figure 7), it is
seen that all three compounds exhibit substantial DNA cleavage.
Compound 5 displays consistent cleaving ability at all three concentra-
tions whereas compounds 4 and 6 show a positive cleaving correlation
with concentration. Based on the number of dark bands (i.e. high DNA
concentration) in the 0–50 bp region, compound 4 at 100 mM (lane 4)
displays the most significant DNA cleaving ability which insinuates that

14
M. B. ISMAIL ET AL.
Figure 7. Lane L: DNA Ladder of known base pair lengths, Lane 1: CT DNA only, Lane 2: DNA
þ 10 mM of 4, Lane 3: DNA þ 50 mM of 4, Lane 4: DNA þ 100 mM of 4; Lane 5: DNA þ 10 mM
of 5, Lane 6: DNA þ 50 mM of 5, Lane 7: DNA þ 100 mM of 5; Lane 8: DNA þ 10 mM of 6,
Lane 9: DNA þ 50 mM of 6 and Lane 10: DNA þ 100 mM of 6.
it is able to generate more reactive oxygen species at high concentrations
than 5 and 6.[22,51]
3.5. DNA interaction studies of chromone Schiff base rhenium
compounds 7–10
Compounds 7–10 induce no significant structural damage of the
DNA–helix as indicated by a lack of substantial red or blue shifts of the
peak maxima (see Figures S14–S17). Compounds 7–9 display hypochrom-
ism (7: 8%, 8: 8% and 9: 42%) whereas compound 10 exhibits hyperchrom-
ism (13%) as well as two isosbestic points at 303 and 349 nm. Isosbetic
points are commonly seen in DNA binding titrations but do not infer
binding mode. Typical examples of this phenomenon are observed for the
titrations of octahedral Schiff base iron(II) compounds [Fe(bsal)2]ꢆ2H2O
and [Fe(bsas)2]ꢆH2O {bsal ¼ 2-[(E)-(5-bromo-2-hydroxybenzylidene)ami-
no]propanoic acid and bsas ¼ 2-[(E)-(5-bromo-2-hydroxybenzylidene)ami-
no]butanedioic acid} with CT–DNA.[53] Since, 7–10 do not display large
hypochromism coupled with bathochromic shifts (indicative of intercal-
ation), they are assigned as DNA groove-binding in nature. With reference
to 10, another molecule that exhibits hyperchromism and assigned as a
groove binding compound is 3,5,6-trichloro-2-pyridinol.[54] Furthermore,
the calculated Kb values of 4.22 ( 0.38)ꢂ104 Mꢁ1, 2.21 ( 0.46)ꢂ105 Mꢁ1,

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
15
Figure 8. Docked position of 7 bound to the minor groove of B–DNA: ball and stick view (left)
and DNA molecular surface view (right).
2.04 ( 0.51)ꢂ105 Mꢁ1 and 1.96 ( 0.25)ꢂ103 Mꢁ1, for 7–10, respectively,
are well within the range of magnitudes previously described (Figure S18).
The relatively small rhenium(I) and -(V) complexes 7–10 [vdW radius
wrt. geometric centre ¼ 7.838 Å (for 7), 8.123 Å (for 8), 8.959 Å (for 9) and
7.994 Å (for 10)] makes this class of compounds groove-binding favourable
(Figures 8, 9, S19 and S20). Compounds 7, 8 and 10 interact with the
minor groove of B–DNA within the AT, AT, GC, CG, GC, CG region
whereas 9 docks within the major groove of the same region. All four com-
pounds display high affinities for DNA based on their global lowest ener-
gies (7: –56.21, 8: –59.72, 9: –45.84, 10: –47.47 kJ molꢁ1) which supports
the moderate to high Kb values attained during the experimental CT–DNA
binding titrations. The structurally similar rhenium(I) compounds 7 and 10
indicate that the chromone moieties interact with the inner hydrophobic
region of B–DNA and the metal carbonyls form hydrogen bonds with the
hydrophilic phosphate backbone between 2.444 and 2.467 Å. In addition,
compound 9 shows the higher energy than the other three compounds
owing to its larger size and weaker interactions: it is stabilized by just a sin-
gle hydrogen bond between a uracil Oketone atom and phosphate oxygen
atom (2.106 Å) whereas 7, 8 and 10 each display at least two stabilizing
hydrogen bonds (2.168–2.467 Å). Furthermore, compound 8 displays a
unique square pyramidal geometry whereby the axial mono

16
M. B. ISMAIL ET AL.
Figure 9. Docked position of 8 bound to the minor groove of B–DNA: ball and stick view (left)
and DNA molecular surface view (right).
oxorhenium(V) core orientates away from the hydrophobic B–DNA inter-
ior with the tetradentate ligand moiety fitting along the carbon–phosphate
backbone via numerous van der Waals interactions, resulting in the most
energetically favourable complex–DNA adduct.
The virtual gel stains for compounds 7–10 clearly indicate that this class
of metal complexes can substantially cleave CT–DNA (Figures 10 and 11).
Upon observation of the lowest (0–100) bp regions of each compound, it is
noted that compounds 8 and 10 cleave DNA to a similar extent across all
three compound concentrations. In contrast, there is a visible increase in
DNA cleavage activity upon increased concentration of 7 and 9. The data
suggest that the production of DNA-damaging reactive oxygen species are
more concentration dependent for 7 and 9 and that at highest concentra-
tion (100 mM), all four compounds are able to cleave DNA to a simi-
lar extent.[42]
4. Conclusion
The molecular docking studies provided fascinating insight into the compu-
tational interactions between the metal compounds and B–DNA structure
at the molecular level. Moreover, correlation could be found between the
calculated global energies of the DNA–metal compound adducts and their
experimental intrinsic binding constants. Of significance was the triphenyl-
phosphine-containing rhenium(V) compounds 1, 4 and 9 displaying the

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
17
Figure 10. Lane L: DNA Ladder of known base pair lengths, Lane 1: CT DNA only, Lane 2: DNA
þ 10 mM of 7, Lane 3: DNA þ 50 mM of 7, Lane 4: DNA þ 100 mM of 7; Lane 5: DNA þ 10 mM
of 8, Lane 6: DNA þ 50 mM of 8, Lane 7: DNA þ 100 mM of 8; Lane 8: DNA þ 10 mM of 9,
Lane 9: DNA þ 50 mM of 9 and Lane 10: DNA þ 100 mM of 9.
Figure 11. Lane L: DNA Ladder of known base pair lengths, Lane 1: CT DNA only, Lane 2: DNA
þ 10 mM of 10, Lane 3: DNA þ 50 mM of 10, Lane 4: DNA þ 100 mM of 10.

18
M. B. ISMAIL ET AL.
ability to dock within either major or minor B–DNA grooves. It is also
noted that the CT–DNA cleaving capability of the major groove binding
compounds 1 and 9 do not significantly differ from the minor groove
binding compound 4. In addition, the square pyramidal geometry of the
oxorhenium(V) complex 8 maximizes contact interaction between its tetra-
dentate organic chelator and the B–DNA phosphate backbone, allowing an
extension of the chelator to interact with the B–DNA interior. This
research finding provides new scope for research in designing
oxorhenium(V) complexes with similar chelating ligands whereby the
resultant metal complexes could potentially circumvent the weak computa-
tional B–DNA interactions of these class of rhenium complexes as well as
culminating low experimental intrinsic binding constants. Another interest-
ing molecular docking research finding is with the competitive polarity
interactions of the uracil derivatives (for 1 and 2) to B–DNA which pro-
vides evidence for the low Kb values of 1 and 2. Excluding compound 8,
the rhenium(I) compounds generally display superior affinities for DNA
when compared to the rhenium(V) compounds stemming from their
smaller vdW radii (wrt their geometries) and stronger bonding patterns
between chelating ligands and the hydrophobic DNA interior.
Funding
We are grateful to the University of KwaZulu-Natal, the National Research Foundation of
South Africa and the Deutscher Akademischer Austauschdienst (DAAD) for finan-
cial support.
References
[1] Hall, D.; Holmlin, R.; Barton, J. K. Oxidative DNA Damage Through Long-Range
Electron Transfer. Nature 1996, 382, 731–735. DOI: 10.1038/382731a0.
[2] Yang, X.; Feng, J.; Zhang, J.; Zhang, Z.; Lin, H.; Zhou, L.; Yu, X. Synthesis, DNA
Binding and Cleavage Activities of the Copper(II) Complexes of Estrogen-
Macrocyclic Polyamine Conjugates. Bioorg. Med. Chem. 2008, 16, 3871–3877. DOI:
10.1016/j.bmc.2008.01.037.
[3] Clarke, M. J.; Sadler, P. J. Metallopharmaceuticals I: DNA Interactions; Springer:
New York, 1999.
[4] Pages, B. J.; Ang, D. L.; Wright, E. P.; Aldrich-Wright, J. R. Metal Complex
Interactions with DNA. Dalton Trans. 2015, 44, 3505–3526. DOI: 10.1039/
C4DT02700K.
[5] Zeglis, B. M.; Pierre, V. C.; Barton, J. K. Metallo-Intercalators and Metallo-Insertors.
Chem. Commun. 2007, 28, 4565–4579. DOI: 10.1039/b710949k.
[6] Zhang, Q.; Liu, J.; Chao, H.; Xue, G.; Ji, L. DNA-Binding and Photocleavage Studies
of Cobalt(III) Polypyridyl Complexes: [Co(Phen)2IP]3þ and [Co(Phen)2PIP]3þ. J.
Inorg. Biochem. 2001, 83, 49–55. DOI: 10.1016/S0162-0134(00)00132-X.

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
19
[7] Lee, L. C.-C.; Leung, K.-K.; Lo, K. K.-W. Recent Development of Luminescent
Rhenium(I) Tricarbonyl Polypyridine Complexes as Cellular Imaging Reagents,
Anticancer Drugs, and Antibacterial Agents. Dalton Trans. 2017, 46, 16357–16380.
DOI: 10.1039/C7DT03465B.
[8] Gabr, M. T.; Pigge, F. C. Rhenium Complexes of Bis(Benzothiazole)-Based
Tetraarylethylenes as Selective Luminescent Probes for Amyloid Fibrils. Chem. Eur.
J. 2018, 24, 11729–11737. DOI: 10.1002/chem.201801801.
[9] Giffard, D.; Fischer-Fodor, E.; Vlad, C.; Achimas-Cadariu, P.; Smith, G. S.
Synthesis and Antitumour Evaluation of Mono- and Multinuclear [2 þ 1]
Tricarbonylrhenium(I) Complexes. Eur. J. Med. Chem. 2018, 157, 773–781. DOI: 10.
1016/j.ejmech.2018.08.011.
[10] Haase, A. A.; Bauer, E. B.; Ku€hn, F. E.; Crans, D. C. Speciation and Toxicity of
Rhenium Salts, Organometallics and Coordination Complexes. Coord. Chem. Rev.
2019, 394, 135–161. DOI: 10.1016/j.ccr.2019.05.012.
[11] Bauer, E. B.; Haase, A. A.; Reich, R. M.; Crans, D. C.; Ku€hn, F. E. Organometallic
and Coordination Rhenium Compounds and Their Potential in Cancer Therapy.
Coord. Chem. Rev. 2019, 393, 79–117. DOI: 10.1016/j.ccr.2019.04.014.
[12] Ju€rgens, S.; Herrmann, W. A.; Ku€hn, F. E. Rhenium and Technetium Based
Radiopharmaceuticals: Development and Recent Advances. J. Organomet. Chem.
2014, 751, 83–89. DOI: 10.1016/j.jorganchem.2013.07.042.
[13] Abram, U.; Alberto, R. Technetium and Rhenium-Coordination Chemistry and
Nuclear Medical Applications. J. Braz. Chem. Soc. 2006, 8, 1486–1500. DOI: 10.
1590/S0103-50532006000800004.
[14] Makris, G.; Kuchuk, M.; Gallazzi, F.; Jurisson, S. S.; Smith, C. J.; Hennkens, H. M.
Somatostatin Receptor Targeting with Hydrophilic [99mTc/186Re] Tc/Re-Tricarbonyl
NODAGA and NOTA Complexes. Nucl. Med. Biol. 2019, 71, 39–46. DOI: 10.1016/j.
nucmedbio.2019.04.004.
[15] (a) Booysen, I. N.; Ismail, M. B.; Akerman, M. P. Coordination Behavior of
Chromone Schiff Bases Towards the [ReVO]3þ and [ReI(CO)3]þ Cores. J. Coord.
Chem. 2013, 66, 4371–4386; (b) Booysen, I. N.; Ismail, M. B.; Munro, O. Q. Mono-
and Dinuclear Rhenium(I) Compounds with Bidentate Benzimidazole Chelators.
Inorg. Chem. Commun. 2013, 30, 168–172; (c) Booysen, I. N.; Ismail, M. B.; Gerber,
T. I. A.; Akerman, M. P; van Brecht, B. Oxo and Oxofree Rhenium(V) Complexes
with N,O-Donor Schiff Bases. S.A. J. Chem. 2012, 65, 174–177.
[16] (a) Johnson, N. P.; Lock, C. J. L.; Wilkinson, G. Complexes of Rhenium(V). Inorg.
Synth. 1967, 145, 9; (b) Ciani, G.; Alfonso, G. D.; Romiti, P.; Sironi, A.; Freni, M.
Rhenium(V) Oxide Complexes. Crystal and Molecular Structures of the Compounds
Trans-ReI2O(OR)(PPh3)2 (R ¼ Et, Me) and of Their Hydrolysis Derivative
ReIO2(PPh3)2. Inorg. Chim. Acta 1983, 72, 29–37. DOI: 10.1016/S0020-
1693(00)81690-4.
[17] Bruker APEX2, SAINT and SADABS. Bruker AXS Inc., 2010., Madison, Wisconsin,
USA. (software)
[18] Blessing, R. H. An Empirical Correction for Absorption Anisotropy.
Acta Crystallogr.
A Found. Crystallogr. 1995, A51, 33–38. DOI: 10.1107/
S0108767394005726.
[19] Sheldrick, G. M. A Short History of SHELX. Acta Crystallogr. A Found. Crystallogr
2008, 64, 112–122. DOI: 10.1107/S0108767307043930.
[20] Farrugia, L. J. J. WinGX and ORTEP for Windows: An Update. J. Appl. Crystallogr.
2012, 45, 849–854. DOI: 10.1107/S0021889812029111.

20
M. B. ISMAIL ET AL.
[21] Reichmann, M. F.; Rice, S. A.; Thomas, C. A.; Doty, P. A Further Examination of
the Molecular Weight and Size of Desoxypentose Nucleic Acid. J. Am. Chem. Soc.
1954, 76, 3047–3053. DOI: 10.1021/ja01640a067.
[22] Kaplanis, M.; Stamatakis, G.; Papakonstantinou, V. D.; Paravatou-Petsotas, M.;
Demopoulos, C. A.; Mitsopoulou, C. A. Re(I) Tricarbonyl Complex of 1,10-
Phenanthroline-5,6-Dione: DNA Binding, Cytotoxicity, anti-Inflammatory and anti-
Coagulant Effects Towards Platelet Activating Factor. J. Inorg. Biochem. 2014, 135,
1–9. DOI: 10.1016/j.jinorgbio.2014.02.003.
[23] Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; et al.
Gaussian 09 (Revision A.01). Gaussian Inc.: Wallingford, CT, 2009.
[24] Machura, B.; Kruszynski, R. Oxorhenium(V) complexes with Quinoline-2-
Carboxylate Ligand. X-Ray Structure of [ReOCl2(Quin-2-c)(PPh3)] and
[ReOBr2(Quin-2-c)(AsPh3)] Complexes: DFT and TD-DFT Calculations for
[ReOCl2(Quin-2-c)(PPh3)]. Polyhedron 2007, 26, 3686–3694. DOI: 10.1016/j.poly.
2007.03.058.
[25] Brink, A.; Visser, H.; Roodt, A. Novel Imino Rhenium(I) tricarbonyl Complexes of
Salicylidene-Derived Ligands: Synthesis, X-Ray Crystallographic Studies,
Spectroscopic Characterization and DFT Calculations. Polyhedron 2013, 52,
416–423. DOI: 10.1016/j.poly.2012.08.059.
[26] Potgieter, K. C.; Gerber, T. I. A.; Betz, R.; Rhyman, L.; Ramasami, P. Structural and
DFT/TD-DFT Investigation of Tris(Bidentate) Complexes of Rhenium(III)
Synthesized from the Cis-[ReO2]þ Core and Benzenethiol Derivatives. Polyhedron
2013, 59, 91–100. DOI: 10.1016/j.poly.2013.04.038.
[27] Duhovny, D.; Nussinov, R.; Wolfson, H.J. International Workshop on Algorithms in
Bioinformatics (WABI 2002): Algorithms in Bioinformatics, 2002, 185–200.
Schneidman-Duhovny, D.; Inbar, Y.; Nussinov, R.; Wolfson, H.J. PatchDock and
SymmDock: Servers for Rigid and Symmetric Docking. Nucl. Acids. Res. 2005, 33,
W363–W367. DOI: 10.1093/nar/gki481.
[28] Krieger, E.; Vriend, G. You Have Full Text Access to This OnlineOpen Article New
Ways to Boost Molecular Dynamics Simulations. J. Comput. Chem. 2015, 36,
996–1007. DOI: 10.1002/jcc.23899.
[29] Kang, Y.; Ito, A.; Sakuda, E.; Kitamura, N. Diimine Ligand Structure Effects on
Photophysical Properties of Tricarbonyl Rhenium(I) complexes Having Arylborane
Charge Transfer Units. J. Photochem. Photobiol. A 2015, 313, 107–116. DOI: 10.
1016/j.jphotochem.2015.05.034.
[30] Banerjee, S. R.; Levadala, M. K.; Lazarova, N.; Wei, L.; Valliant, J. F.; Stephenson,
K. A.; Babich, J. W.; Maresca, K. P. Zubieta, Bifunctional Single Amino Acid
Chelates for Labeling of Biomolecules with the {Tc(CO)3}þand {Re(CO)3}þ Cores.
Crystal and Molecular Structures of [ReBr(CO)3(H2NCH2C5H4N)], [Re(CO)3
{(C5H4NCH2)2NH}]Br, [Re(CO)3{(C5H4NCH2)2NCH2CO2H}]Br, [Re(CO)3{X(Y)
NCH2CO2CH2CH3}]Br (X ¼ Y ¼ 2-Pyridylmethyl; X ¼ 2-Pyridylmethyl, Y ¼ 2-(1-
Methylimidazolyl)Methyl; X ¼ Y
¼
2-(1-Methylimidazolyl)Methyl), [ReBr(CO)3
and [Re(CO)3{(C5H4NCH2)N(CH2C4H3S)
{(C5H4NCH2)NH(CH2C4H3S)}],
(CH2CO2)}]. J. Inorg. Chem. 2002, 41, 6417–6425. DOI: 10.1021/ic020476e.
[31] Mayer, P.; Gerber, T. I. A.; Buyambo, B.; Abrahams, A. Coordination Behaviour of
Acetylacetone-Derived Schiff Bases Towards Rhenium(I) and (V). Polyhedron 2009,
28, 1174–1178. DOI: 10.1016/j.poly.2009.01.036.

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
21
[32] Zhang, H.; Yang, F.; Wu, Q.; Liao, S.-Y.; Liu, P.; Mei, W.-J.; Li, L.; Zhang, S.-Y.;
Wang, X.-C. Synthesis, DNA-Binding Properties and Quantitative Structure-Activity
Relationships on Ruthenium(II) Complexes with Calf-Thymus DNA. Med. Chem.
(Los Angeles) 2016, 6, 137–142.
[33] Zianna, A.; Psomas, G.; Hatzidimitriou, A.; Lalia-Kantouri, M. Copper(II)
Complexes of Salicylaldehydes and 2-Hydroxyphenones: synthesis, Structure,
Thermal Decomposition Study and Interaction with Calf-Thymus DNA and
Albumins. RSC Adv. 2015, 5, 37495–37511. DOI: 10.1039/C4RA16484A.
[34] Barone, G.; Gambino, N.; Ruggirello, A.; Silvestri, A.; Terenzi, A.; Liveri, V. T.
Spectroscopic Study of the Interaction of NiII-5-Triethyl Ammonium Methyl
Salicylidene Ortho-Phenylendiiminate with Native DNA. J. Inorg. Biochem. 2009,
103, 731–737. DOI: 10.1016/j.jinorgbio.2009.01.006.
[35] Silvestri, A.; Barone, G.; Ruisi, G.; Anselmo, D.; Riela, S.; Liveri, V. T. The
Interaction of Native DNA with Zn(II) and Cu(II) Complexes of 5-Triethyl
Ammonium Methyl Salicylidene Orto-Phenylendiimine. J. Inorg. Biochem. 2007,
101, 841–848. DOI: 10.1016/j.jinorgbio.2007.01.017.
[36] Khan, N. H.; Pandya, N.; Prathap, K. J.; Kureshy, R. I.; Abdi, S. H. R.; Mishra, S.;
Bajaj, H. C. The Interaction of Native DNA with Zn(II) and Cu(II) Complexes of 5-
Triethyl Ammonium Methyl Salicylidene Orto-Phenylendiimine. Spectrochim. Acta
A 2011, 81, 199–208.
[37] Kurdekar, G. S.; Puttanagouda, S. M.; Kulkarni, N. V.; Budagumpi, S.; Revankar,
V. K. Synthesis, Characterization, Antibiogram and DNA Binding Studies of Novel
Co(II), Ni(II), Cu(II), and Zn(II) Complexes of Schiff Base Ligands with Quinoline
Core. Med. Chem. Res. 2011, 20, 421–429. DOI: 10.1007/s00044-010-9330-5.
[38] Chaudhary, K. K.; Mishra, N. A Review on Molecular Docking: Novel Tool for
Drug Discovery. JSM Chem. 2016, 4, 1029.
[39] Thamilarasan, V.; Jayamani, A.; Sengottuvelan, N. Synthesis, Molecular Structure,
Biological Properties and Molecular Docking Studies on MnII, CoII and ZnII
Complexes Containing Bipyridine–Azide Ligands. Eur. J. Med. Chem. 2015, 89,
266–278. DOI: 10.1016/j.ejmech.2014.09.073.
[40] Kyros, L.; Banti, C. N.; Kourkoumelis, N.; Kubicki, M.; Sainis, I.; Hadjikakou, S. K.
Synthesis, Characterization, and Binding Properties Towards CT-DNA and
Lipoxygenase of Mixed-Ligand Silver(I) complexes with 2-Mercaptothiazole and Its
Derivatives and Triphenylphosphine. J. Biol. Inorg. Chem. 2014, 19, 449–464. DOI:
10.1007/s00775-014-1089-6.
[41] Quiroga, E. D.; Cormick, M. P.; Pons, P.; Alvarez, M. G.; Durantini, E. N.
Mechanistic Aspects of the Photodynamic Inactivation of Candida albicans Induced
by Cationic Porphyrin Derivatives. Eur. J. Med. Chem. 2012, 58, 332–339. DOI: 10.
1016/j.ejmech.2012.10.018.
[42] Pratviel, G.; Bernadou, J.; Meunier, B. DNA and RNA Cleavage by Metal
Complexes. Adv. Inorg. Chem. 1998, 45, 251–312.
[43] Xu, Z.-H.; Chen, F.-J.; Xi, P.-X.; Liu, X.-H.; Zeng, Z.-Z. Synthesis, Characterization,
and DNA-Binding Properties of the Cobalt(II) and Nickel(II) Complexes with
Salicylaldehyde 2-Phenylquinoline-4-Carboylhydrazone. J. Photochem. Photobiol. A
2008, 196, 77–83. DOI: 10.1016/j.jphotochem.2007.11.017.
[44] Barton,
J.
K.;
Danishefsky,
A.
T.;
Goldberg,
J.
M.
Tris(Phenanthroline)Ruthenium(II): Stereoselectivity in Binding to DNA. J. Am.
Chem. Soc. 1984, 106, 2172–2176. DOI: 10.1021/ja00319a043.

22
M. B. ISMAIL ET AL.
[45] Chow, C. S.; Barton, J. K. Transition Metal Complexes as Probes of Nucleic Acids.
Methods Enzymol. 1992, 212, 219–242.
[46] Shakir, M.; Abbasi, A.; Khan, A. U.; Khan, S. N. Synthesis and Spectroscopic Studies
on the Schiff Base Ligand Derived from Condensation of 2-furaldehyde and 3,3’-dia-
minobenzidene, L and its complexes with Co(II), Ni(II), Cu(II) and Zn(II): com-
parative DNA binding studies of L and its Cu(II) and Zn(II) complexes.
Spectrochim. Acta. A Mol. Biomol. Spectrosc. 2011, 78, 29–35. DOI: 10.1016/j.saa.
2010.02.034.
[47] Arjmand, F.; Sayeed, F.; Muddassir, M. Synthesis of New Chiral Heterocyclic Schiff
Base Modulated Cu(II)/Zn(II) Complexes: Their Comparative Binding Studies with
CT-DNA, Mononucleotides and Cleavage Activity. J. Photochem. Photobiol. B 2011,
103, 166–179. DOI: 10.1016/j.jphotobiol.2011.03.001.
[48] Shi, J.-H.; Chen, J.; Wang, J.; Zhu, Y.-Y. Binding Interaction between Sorafenib and
Calf Thymus DNA: Spectroscopic Methodology, Viscosity Measurement and
Molecular Docking. Spectrochim. Acta Part A 2015, 136, 443–450. DOI: 10.1016/j.
saa.2014.09.056.
[49] Shi, J.-H.; Liu, T.-T.; Jiang, M.; Chen, J.; Wang, Q. Characterization of Interaction
of Calf Thymus DNA with Gefitinib: Spectroscopic Methods and Molecular
Docking. J. Photochem. Photobiol. B 2015, 147, 47–55. DOI: 10.1016/j.jphotobiol.
2015.03.005.
[50] Alonso, H.; Bliznyuk, A. A.; Gready, J. E. Combining Docking and Molecular
Dynamic Simulations in Drug Design. Med. Res. Rev. 2006, 26, 531–568. DOI: 10.
1002/med.20067.
[51] Shahabadi, N.; Darabi, F.; Maghsudi, M.; Kashanian, S. DNA Binding and Gel
Electrophoresis Studies of a Copper (II) Complex Containing Mixed Aliphatic and
Aromatic Dinitrogen Ligands, DNA. Cell Biol. 2010, 29, 329–336. DOI: 10.1089/dna.
2009.1001.
[52] Chen, J.; Huang, Y.-W.; Liu, G.; Afrasiabi, Z.; Sinn, E.; Padhye, S.; Ma, Y. The
Cytotoxicity and Mechanisms of 1,2-Naphthoquinone Thiosemicarbazone and Its
Metal Derivatives against MCF-7 Human Breast Cancer Cells. Toxicol. Appl.
Pharmacol. 2004, 197, 40–48. DOI: 10.1016/j.taap.2004.02.004.
[53] Abdel-Rahman, L. H.; El-Khatib, R. M.; Nassr, L. A. E.; Abu-Dief, A. M.; Ismael,
M.; Seleem, A. A. Metal Based Pharmacologically Active Agents: Synthesis,
Structural Characterization, Molecular Modeling, CT-DNA Binding Studies and in
Vitro Antimicrobial Screening of Iron(II) Bromosalicylidene Amino Acid Chelates.
Spectrochim. Acta A 2014, 117, 366–378. DOI: 10.1016/j.saa.2013.07.056.
[54] Kashanian, S.; Shariati, Z.; Roshanfekr, H.; Ghobadi, S. DNA Binding Studies of
3,5,6-Trichloro-2-Pyridinol Pesticide Metabolite. DNA Cell Biol. 2012, 31,
1341–1348. DOI: 10.1089/dna.2012.1662.