Synopsis
Synthesis, spectral, structural, electrochemical and
metallonuclease activities of copper(II) and nickel(II) complexes
with N/O containing ligands
SYNOPSIS SUBMITTED TO ALAGAPPA UNIVERSITY IN PARTIALFULFILMENT
FOR THE AWARD OF THE DEGREE OF
DOCTOR OF PHILOSOPHYINCHEMISTRY
ByA. Jayamani(Reg. No: 0321)
Dr. N. Sengottuvelan, M.Sc., B.Ed., Ph.D., Research
Supervisor
Department of Industrial ChemistrySchool of Chemical
SciencesAlagappa University(Re-accredited with A Grade by
NAAC)Karaikudi - 630 003Tamil NaduIndia
May 2015 Synopsis
5
Synthesis, spectral, structural, electrochemical and
metallonuclease activities of copper(II) and nickel(II) complexes
with N/O containing ligandsArtificial metallonucleases are in high
demand as cellular regulators of DNA for therapeutic or biochemical
purposes [1]. Metal complexes containing site-specific
substructures and multiple reactive sites constitute a group of
promising candidates for nucleases because of their electronic and
structural advantages [2]. Moreover, these complexes generate
highly cationic species that favor the electrostatic attraction to
anionic phosphate backbone of DNA. Incorporation of a DNA-targeting
moiety into the ligands can improve the selectivity of
metallonucleases [3]. Chemical nucleases are redox active
coordination complexes that cleave DNA by an oxidative pathway.
Direct scission of DNA by oxidizing or hydrolytic agents is the
subject matter for several current researches in bioinorganic
chemistry. Redox-active transition metal complexes in the presence
of oxidants have been extensively used for DNA cleavage reactions.
Among the transition metal based cleaving reagents, copper and
nickel were essential elements which can be estimated by the wide
range of Cu/Ni proteins and enzymes playing different roles in
biological systems [4]. There is an exigency to identify effective
metal-based therapeutics, particularly those that overcome both
inherent and acquired resistance to drug therapy which show
improved therapeutic properties, stimulating the ongoing
investigations of alternative molecular targeted metal-based drugs
[5]. Medicinal inorganic chemistry is a thriving interdisciplinary
research area [69] which offers exciting possibilities for the
design of novel metal-based therapeutic /diagnostic agents with
unique mechanisms of action [10].This Ph. D work mainly focuses on
the synthesis, spectral, structural, electrochemical and
metallonuclease activities of copper(II) and nickel(II) complexes
with bidentate ligands containing N2/ O2/N2O2 donors or
tetra-dentate acyclic Schiffs base ligands containing N4
coordinating atoms. The protein binding, DNA binding, molecular
docking and antimicrobial properties of these complexes were also
studied.Chapter IIntroductionThis chapter deals with general
introduction to medicinal application of transition metal
complexes, especially copper and nickel. It also describes the
types of ligands, enzymatic activity of copper and nickel
complexes, geometry and electrochemical properties of complexes,
bimolecules and their interactions with metal complexes,
metallonuclease activity of copper and nickel complexes, and
antimicrobial properties. It also critically reviews the reported
copper and nickel complexes related to their N/O chelating ligand
and their properties pertaining to bidendate and Schiffs base
complexes. Literature reports show that spectral, structural,
metalonuclease properties and medicinal applicability of the
complexes are influenced by the nature of coordination geometry of
the complexes and substituent in the ligand framework. This chapter
ends with list of references of this part.Chapter IIAim and
scopeThe second chapter of the thesis explains the scope of the
present work. The reactivity of metal complexes towards DNA and
protein BSA is important in understanding the mechanism of binding
and in the rational design of metallo-drugs. Metal complexes
containing planar heterocyclic aromatic ligands, such as 2,
2-bipyridine and 2, 2-biimidazole or simple aromatic
salicylaldehyde derivatives or bulky aromatic naphthaldehyde
derivative, have been at the forefront of these investigations
owing to their unusual electronic properties and diverse chemical
reactivity. Several metal complexes of Schiffs bases derived from
salicylaldehyde and amines were also reported and some of them have
been proven to be efficient metallonuclease and as novel tumour
chemotherapeutic agents. In order to expand the knowledge in this
field, we synthesized, characterized the copper(II) and nickel(II)
complexes with potential bidendate ligands, mixed ligand and
Schiffs base ligands. The spectral, electrochemical, biomolecular
interactions, metallonuclease activity and antimicrobial properties
of the complexes were studied by using various analytical
tools.Chapter IIIExperimental detailsThe third chapter deals with
the experimental details and synthetic methodology of copper(II)
and nickel(II) complexes with potential bidendate ligands which
forms N4, O4, N2O2 type of coordinations and four Schiffs base
ligands with four N-donor atoms of bappz and free phenlolic
hydroxyl group of hydroxy aldehyde compounds. This chapter also
describes the various instrumental methods used during the course
of study.The electronic spectra were recorded on a Shimadzu
UV3101PC spectrophotometer. The IR spectra were recorded in 4000400
cm1 region using KBr pellets on a Bruker EQUINOX-55 spectrometer.
Fluorescence spectra were recorded on Elico SL-174
spectrofluorometer. The circular dichroism (CD) spectra were
recorded on Jasco J-810 spectropolarimeter. Elemental analyses were
carried out on an Elementar vario MACRO cube elemental analyzer.
The Electron Paramagnetic Resonance (EPR) spectra were recorded at
liquid nitrogen temperature with Varian E-112 X-band spectrometer
operating at 910 GHz (SAIF, IIT Bombay, India). The DNA cleavage
studies were visualized and photographed on BIO RAD Gel DOC XR+
with image lab-3.0 software. A Biologic CHI604D electrochemical
analyzer was used for studying the electrochemical behavior of
complexes using a three-electrode cell in which a glassy carbon
electrode was the working electrode, a saturated Ag/AgCl electrode
was the reference electrode and a platinum wire was used as an
auxiliary electrode in nitrogen atmosphere. The concentration of
complexes was 103 M in dimethylformamide (DMF) and
tetra(n-butyl)ammonium perchlorate (TBAP) (101 M) was used as the
supporting electrolyte. Safety note: Perchlorate salts of metal
complexes are potentially explosive and should be handled with
care. The rigid molecular docking studies were performed by using
HEX 8.0 software.Chapter IVResults and discussionsThe detailed
results obtained from spectral, structural, electrochemical,
BSA/DNA binding, DNA cleavage activity and antimicrobial studies of
all the synthesized complexes are well discussed in this
chapter.Synthesis of copper(II) and nickel(II) complexes with
heterocyclic bidentate ligands containing N2 chelating donor setThe
synthesis of Copper(II) complexes (15) of bipyridine was carried
out using a common procedure by the reaction of stoichiometric
amount of chloride, perchlorate, acetate salts of copper,
bipyridine and sodium perchlorate in methanol (Scheme 1).
The synthesis of Cu(II) and Ni(II) complexes (6 and 7,
respectively) of biimidazole were carried out using a common
procedure by the reaction of stoichiometric amounts of copper(II)
perchlorate hexahydrate, nickel(II) perchlorate hexahydrate with
biimidazole in methanol (Scheme 2).
Synthesis of copper(II) and nickel(II) complexes with O2 donor
set ligands The synthesis of copper(II) and nickel(II) complexes of
5-methyl salicylaldehyde, 5-bromosalicylaldehyde,
5-nitrosalicylaldehyde and 2-hydroxy-1-napthaldehyde was carried
out using a common procedure by the reaction of stoichiometric
amounts of copper(II)/ nickel(II) perchlorate salts with respective
ligands in ethanol (Scheme 3).
Synthesis of copper(II) complexes with mixed bidentate (N2O2
chelating) ligands The synthesis of the dimeric copper(II)
complexes were carried out using a common procedure by reaction of
stoichiometric amounts of copper(II) perchlorate salt and
respective ligands in methanol. The analytical data obtained for
complexes 1623 are consistent with the formation of dimeric
copper(II) complexes (Scheme 4 and 5).
Synthesis of acyclic Schiffs base ligands L1 - L4The Schiffs
base ligands L1
[N,N-bis(2-hydroxy-5-methylbenzyl)-1,4-bis(3-iminopropyl)piperazine],
L2 [N,N-bis(2-hydroxy-5-bromobenzyl)-1,4-bis(3-iminopropyl)
piperazine], L3
[N,N-bis(2-hydroxy-5-nitrobenzyl)-1,4-bis(3-iminopropyl)
piperazine] and L4
[N,N-bis(2-hydroxy-1-naphthyl)-1,4-bis(3-iminopropyl)piperazine]
have been synthesized as given in scheme 6.
Synthesis of mononuclear copper(II) and nickel(II) complexes
with Schiffs base ligandsThe mononuclear copper(II) complexes
[CuL14](ClO4)2 were synthesized from ligand (L1-4) with copper(II)
perchlorate hexahydrate in 1:1 molar ratio. (Scheme 7) and
nickel(II) complexes [Ni(bappz)](ClO4)2, [NiL1-4](ClO4)2 were
synthesized from ligand bappz, (L1-4), respectively, with
nickel(II) perchlorate hexahydrate in 1:1 molar ratio. (Scheme
8)
Crystal structureThe single crystals of Schiffs base ligands
(L1, L2 and L4), copper(II) complexes 1-6 and 16-19, nickel(II)
complexes 7, 12, 13 and 28 were obtained and the structures were
solved by X-ray crystal structure analysis.i) The Schiffs base
ligands L1 and L2 crystallize in monoclinc P21/c space group but
ligand L4 crystallize in monoclinic P21/c space group as a dimeric
ligand.ii) In the crystal structure of copper(II) complexes, the
geometry of Cu(II) ion in 1, 5 and 6 were distorted square
pyramidal with N4O coordination; in 2 and 3 were distorted trigonal
bipyramidal with N4O coordination; in 4, 16, 18 and 19 were
distorted octahedral with N2O4 coordination; and in 17 was
distorted square planar geometry with N2O2 coordination. iii) In
the crystal structure of nickel(II) complexes, the geometry of
Ni(II) ion in 7 was distorted octahedral with N4O2 coordination; in
12 and 13 were square planar with O4 coordination; and in 28 was
distorted square planar with N4 coordination. Spectral
characterizationsThe ESI mass spectral data of the copper(II) and
nickel(II) complexes and ESR spectra for all copper(II) complexes
were obtained and showed good agreement with the proposed structure
of the complexes.The 1H NMR and 13C NMR spectra of the ligands were
analyzed to confirm the formation of Schiffs base ligands. The IR
spectra of complexes 15 show band near 16001639 cm1 for (C=N) group
of bipyridine, at 3650 and 3625 cm1 to the bridging OH group (4 and
5), at 3189 cm1 for N-H stretching and a band at 1315 cm1 for N-H
bending vibrations (6 and 7). The IR spectra of complexes 811 has
bands near 3095-3070 cm1 and 2895-2876 cm1for aromatic and aldehyde
CH stretching and the band at 461-568 cm1 for metal-oxygen (MO).
The IR spectra of complexes 1623 a band near 1690 cm1 for C=O
(aldehyde), 1620-1650 cm1 for (C=N) group, 1530-1560 cm1 for the
phenoxide bridging with the metal ions. The IR spectrum of
complexes 2432 show band in the region of 1620-1650 cm1 for (C=N),
1000-1100 cm1 and 625 cm1 for antisymmetric stretch and
antisymmetric bend of the perchlorate ions, respectively. The
electronic spectra for all complexes were obtained in DMF solution.
In the UV region of all complexes the peaks near 240290 nm due to *
transition and peaks near 300 - 450 nm due to n */ligandmetal
charge transfer/metalligand charge transfer transitions. The
copper(II) complexes of bidendate N2 donar ligands show d-d bands
around 518 - 636 nm, characteristic of distorted square
pyramidal/trigonal bipyramidal geometry (1-3, 5 and 6) and 662 nm
of distorted octahedral geometry (4). The copper(II) complexes of
O2 donar ligands show d-d bands around 520-560 nm characteristic of
square planar geometry (811). The mixed ligand copper(II) complexes
show d-d bands around 504-708 nm characteristic of distorted square
planar/octahedral geometry (1619). The Schiffs base copper(II)
complexes show d-d bands around 568-594 nm which may be distorted
square planar geometry (2427). The nickel(II) complexes of
biimidazole show d-d bands at 1013, 960 and 593 nm which is
characteristic of distorted octahedral geometry (7). The nickel(II)
complexes of O2 donar ligands (1215), tetradentate bappz (28) and
tetradentate acyclic Schiffs base ligands (2932) show d-d bands
around 518-594 nm characteristic of square planar
geometry.Hirshfeld surface calculationsThe 2D full and resolved HH,
NH and OH fingerprint plots of the copper(II) and nickel(II)
complexes of N2 donar ligands conveys that the complex formation of
ligands with metal ions destroy the stacking interactions in
bipyridine/biimidazole, and perchlorate and hydroxyl group cause a
larger influence than other co-ligands. Electrochemical studies(i)
At cathodic potentialThe mononuclear copper(II) complexes of
bidendate N2 donar ligands exhibit one electron quasi-reversible
redox wave at cathodic potential in the region Epc = 0.63 to 0.76 V
and the binuclear copper(II) complexes exhibit two one electron
quasi-reversible redox waves in the region of E1pc = 0.72 to 0.73 V
& E2pc = 1.24 to 1.45 V.The mononuclear copper(II) complexes of
bidendate O2 donar ligands exhibit one electron quasi-reversible
redox wave at cathodic potential in the region at E1pc = 0.74 to
0.77 V. The mixed ligand copper(II) complexes exhibit one electron
quasi-reversible redox wave at cathodic potential in the region at
E1pc = 0.74 to 0.90 V. The copper(II) complexes of Schiffs base
ligands shows one electron quasi-reversible redox wave at cathodic
potential in the region at E1pc = 0.71 to 0.85 V.The mononuclear
nickel(II) complexes exhibit one electron quasi-reversible redox
wave at cathodic potential in the region at Epc = 0.61 to 0.80 V.
The nickel(II) complexes of Schiffs base ligands and bappz shows
one electron quasi-reversible redox wave at cathodic potential in
the region at Epc = 0.69 to 1.65 V.(ii) At anodic potentialAll the
mononuclear nickel(II) complexes show quasireversible one electron
transfer at anodic potential (Epa = 1.28 V for biimidazole complex,
Epa = 1.08 to 1.44 V for bidendate ligands with O2 donar set
complexes and Epa = 0.88 to 1.21 V for Schiffs base
complexes).pH-controlled molecular ion motionThe copper(II) and
nickel(II) complexes of Schiffs base ligands were analysed for
molecular motions by absorption spectroscopy. Titration of the
complexes with base induces colour change of the solution and also
results in the considerable change in absorption spectrum. The
increase in d-d band of the complexes indicates that the colour and
spectral changes associated to the deprotonation process. The
change of the position of copper/nickel atom from N4 compartment to
N2O2 compartment was achieved by varying the pH of the complex
solution.BSA binding studiesThe BSA binding studies of the
complexes copper(II) and nickel(II) complexes were carried out
using fluorescence spectroscopy and binding constant values were
determined. The association binding constant for copper(II) and
nickel(II) complexes of N2 donar ligands were in the range of 1.65
104 to 3.59 104 M-1, for copper(II) and nickel(II) complexes of O2
donar ligands were in the range of 7.05 104 to 4.68 105 M-1 and for
Schiffs base copper(II) and nickel(II) complexes were in the range
of 1.27 104 to 1.58 105 M-1. The binding constant values were
comparitively higher for complexes with bidentate O2 donar ligands
than that of other complexes due to the difference in planarity of
the complexes. DNA binding studies(i) Absorption spectroscopy The
DNA binding ability of the complexes were investigated using
absorption spectroscopy and binding constant values were
determined. The Kb values for bidendate copper(II) and nickel(II)
complexes of N2 donar ligands were found to be in the range of 2.75
103 to 1.03 105 M-1 and of O2 donar ligands were in the range of
1.16 104 to 6.72 104 M-1. For mixed ligand copper(II) complexes the
Kb values were in the range of 2.56 103 to 5.10 104 M-1 and for
Schiffs base copper(II) and nickel(II) complexes the Kb values were
in the range of 1.63 103 to 6.20 104 M-1.(ii) Fluorescence
spectroscopyThe DNA binding ability of the complexes were
investigated using fluorescence spectroscopy and linear SternVolmer
quenching constant (Ksv) values were determined. The Ksv values for
bidendate copper(II) and nickel(II) complexes of N2 donar ligands
were found to be in the range of 3.93 104 M1 to 7.86 105 M1 and of
O2 donar ligands were in the range of 1.88 103 M1 to 1.41104 M1.
For mixed ligand copper(II) complexes the Ksv values were in the
range of 2.89 103 M1 to 2.60 104 M1 and for Schiffs base copper(II)
and nickel(II) complexes the Ksv values were in the range of 2.33
103 M-1 to 1.51 105 M-1.
(iii) Circular dichroism spectroscopyAll the complexes have
shown moderate shift in the positive CD signal at 272-276 nm with
slight decrease/increase in intensity for both the negative
ellipticity band near 245 nm and the positive ellipticity band near
275 nm. The binding of complexes with ctDNA was found to be in
groove and electroststic binding for copper(II) and nickel(II)
bidendate N2 / O2 chelating ligands but in the case of mixed ligand
copper(II) complexes and Schiffs base copper(II)/ nickel(II)
complexes the mode of binding vary from groove binding to
itercalation depending on the planarity, hetero atoms and
aromaticity of the ligand molecules.Molecular docking studiesAll
the complexes were docked within the DNA duplex of sequence
d(CGCGAATTCGCG)2 dodecamer (PDB ID: 1BNA) in order to predict the
chosen binding site along with preferred orientation of the ligand
and the relative binding energies were calculated. DNA cleavage
ability of complexesThe DNA cleavage was carried out for all the
complexes and their mechanistic pathway was also studied. All the
complexes show no cleavage without the addition reactive agents
(H2O2/MPA), the cleavage process was concentration dependent and
all complexes cleave efficiently at 200 M concentration. All the
copper(II) complexes cleaves pBR322 DNA in the presence of
3-mercaptopropionic acid and for the cleavage process to occur the
singlet oxygen plays a vital role for formation of involvement of
copper-oxo intermediate. All the nickel(II) complexes cleaves
pBR322 DNA in the presence of hydrogen peroxide and cleavage
process preferentially proceeded by a hydroxyl radical mechanism
with OH formation. Oxidative cleavage of plasmid DNA species may
lead to the formation of hydrogen peroxide (H2O2), and/or hydroxyl
radical (HO) species, which cause damage to the sugar and/or
base.Antimicrobial studiesAll the complexes were screened for
antimicrobial analysis with four pathogenic bacteria species and
two fungal species and the obtained results as zone of inhibiton
have also been compared with those of the standard drugs, amikacin
and ketokonazole for bacteria and fungi, respectively. Chapter
VSummary and conclusionsThe summary of the present work is
presented in this chapter. The brief idea about the future course
of the task is also offered.The thesis finally ends with list of
references that is cited in chapter 3 and 4 of this thesis.
References1. L. J. K. Boerner, J. M. Zaleski, Curr. Opin. Chem.
Biol., 2005, 9, 135.2. Q. Jiang, N. Xiao, P. F. Shi, Y. G. Zhu, Z.
J. Guo, Coord. Chem. Rev., 2007, 251, 1951.3. T. Ito, S.
Thyagarajan, K. D. Karlin, S. E. Rokita, Chem. Commun., 2005,
4812.4. W. Kaim, J. Rall, Angew. Chem. Int. Ed. Engl., 1996, 35,
43.5. T. Storr, K. H. Thompson, Chem. Soc. Rev., 2006, 35, 534.6.
T. W. Hambley, Science, 2007, 318, 1392.7. S. H. Rijt, P J. Sadler,
Drug Discov. Today, 2009, 14, 1089.8. J. L. Sessler, Med. Inorg.
Chem. in ACS symp. Ser., 2005, 930, 453.9. L. Ronconi, P. J.
Sadler, Coord. Chem. Rev., 2008, 252, 2239.10. N. Farrel, Compr.
Coord. Chem. II., 2003, 9, 809
List of papers published from this work1. A. Jayamani, N.
Sengottuvelan, S. K. Kang, Y-I. Kim, Studies on nucleic
acid/protein interaction, molecular docking and antimicrobial
properties of mononuclear nickel(II) complexes of piperazine based
Schiffs base, Inorganic Chemistry Communications, 48 (2014)
147152.2. A. Jayamani, N. Sengottuvelan, G. Chakkaravarthi,
Synthesis, structural, electrochemical, DNA interaction,
antimicrobial and molecular docking studies on dimeric copper(II)
complexes involving some potential bidentate ligands, Polyhedron,
81 (2014) 764776.3. A. Jayamani, V. Thamilarasan, V. Ganesan, N.
Sengottuvelan, P. Manisankar, S. K. Kang, Y-I. Kim, Synthesis of
mononuclear copper(II) complexes of acyclic Schiffs base ligands:
Spectral, structural, electrochemical, antibacterial, DNA binding
and cleavage activity, Spectrochimica Acta Part A: Molecular and
Biomolecular Spectroscopy, 122 (2014) 365374. 4. B. Saravanan, A.
Jayamani, N. Sengottuvelan, G. Chakkaravarthi, V. Manivannan,
Di--hydroxido-4O:O-di--perchlorato-4O:O-bis[(2,2-bipyridine-2N,N)-copper(II)],
Acta Crystallographica E, 69 (2013) m600.5. A. Jayamani, V.
Thamilarasan, V. Ganesan, N. Sengottuvelan, Structural,
electrochemical, DNA binding and cleavage properties of nickel(II)
complex [Ni(H2biim)2(H2O)2]2+ of 2,2'-biimidazole, Bull. Korean
Chem. Soc., 24 (2013) 1-8.