Copper(II) complexes as Anticancer agents

Ph. D. Viva Voce Examination University of Madras

Interaction of Copper(II) Complexes of Bi- and

Tridentate Ligands with DNA and their Anti-proliferative

Effects on Osteosarcoma Cancer Cell

S Rajalakshmi

Chemical Laboratory

Structure of Thesis

Chapter 1 Introduction

Chapter 2 Analytical techniques and experimental details

Chapter 3 Interaction of mixed ligand copper(II) complexes with DNA

and its anti-proliferative effects

Chapter 4 DNA condensation ability- benzimidazolylterpyridine

copper(II) complexes & its anti-proliferative effects

Chapter 5 Investigation of interaction of copper(II) complexes of

thiophenemethanamine derivatives with DNA & their anti-

proliferative effects

Chapter 6 Summary and conclusions

2

Chapter 1

INTRODUCTION

3

Need of Metal Ions in Biological System?

• Nature itself has incorporated many metal ions in biological system

• Metal ions must be obtained for growth & development

• Metal ions play tremendous role in biological system predominantly

in the cationic form 4

Need of Metal Ions in Biological System?

• Metal ions can have structural role, functional role & both

Metal Function

Na+, K+ Charge carrier, osmotic balance

Mg2+, Zn2+ Structural hydrolase, isomerase

Ca2+ Structural, charge carrier

V2+, Mo3+ Nitrogen fixation, oxidase

Mn2+ Photosynthesis, structural, oxidase

Fe2+, Cu2+ Dioxygen transport & storage, electron transfer, oxidase

Ni2+ Hydrogenase, Hydrolase

Knowing the indispensable role of metal ion in biological system

the use of metal complexes as therapeutic agent is the natural

step in medicinal chemistry

5

Pioneers of Metal Based Drugs

Salvarsan - Drug

• Treatment of syphilis

• Prof. Ehlrich Noble prize

- Immunochemistry

Aurothioglucose Sodium aurothiopropanol

sulfonate

Gold complexes – Chrysotherapy- Rheumatoid Arthritis

6

Anticancer Agents : Platinum Complexes

Lobaplatin

Cisplatin Carboplatin Nedaplatin

Oxaliplatin

7

Anticancer Agents: Non-Platinum Complex

KP1019 Tamoxifene

Casiopeinas

NAMI-A

Still there is a need for alternative

anti-cancer agents based on

transition metal complexes

8

• Copper is one of the third most abundant transition metal in living

systems

• Plants/Animals : Electron transfer/O2-carrying

• Cu-proteins and enzymes

Cytochrome oxidase O2→H2O

Tyrosinase, phenol oxidase ox. of phenols

Ceruloplasmin Fe(II) → Fe(III)

Blue proteins Electron transfer

Superoxide dismutase Elimination of O2-

Hemocyanin O2 transport

• Biologically accessible redox potential

Cu(s)→ Cu2++2e− (-0.34 V)

Copper based complexes as an alternative

9

To design and synthesis planar aromatic to non-planar aliphatic

ligands and coordination with copper(II) salts for therapeutic

applications

Analyzing the DNA binding ability of the synthesized copper

complexes

Evaluating the synthetic nuclease activity of the synthesized

copper complexes

Deriving the relationship between mode of binding of copper

complexes to DNA against cytotoxic effects on cancerous and

normal cell lines

Objective

10

Chapter 2

Analytical Techniques and

Experimental Details

11

Analytical Techniques - Characterization

Ligands Metal complex

FT-IR spectroscopy Elemental analysis

Electronic absorption

spectroscopy

FT-IR spectroscopy

Fluorescence spectroscopy ESI-Mass spectrometry

Nuclear magnetic resonance

spectroscopy

Electron paramagnetic

resonance spectroscopy

ESI-Mass spectrometry


spectroscopy

Fluorescence spectroscopy

Single crystal X-ray diffraction

12

Analytical Techniques: Metal Complex-

Biomolecules Interaction

Metal complex-DNA

Binding studies

Effect of MC on DNA

Condensation and

Cleavage studies

Anti-proliferative

studies


spectroscopy

Electrophoretic mobility

assay

Microscopy

Fluorescence

spectroscopy

Dynamic light scattering

spectroscopy


spectroscopy

Rheological

measurements

Fluorescence

microscopy

Circular dichroism

spectroscopy

MTT assay &

Apoptotic assay

Molecular docking

studies 13

Schematic Representation: Synthesis of

Ligands

ptpy - pyridine-2-carbaldehyde (L2); meotpy – 4-methoxybenzaldehyde

(L3); benzimidazole-2-aldehyde – bitpy (L4) (i)

Synthesis of terpyridyl derivatives

imidazole – ithma (L5)

pyridyl– pythma (L6)

benzimdiazolyl – bzthma (L7) (ii)

(L1)

14

Synthesis of thiophenemethanamine derivatives

(i) G. W. V. Cave, C. L. Raston, J. Chem. Soc. Perkin Trans. I, 2001, 3258. (ii) P. Kumar et al., Dalton Trans. 2012, 41, 7573-7581

4’X-terpy + Cu(NO3)2.3H2O + dmp → [Cu(4’X-terpy)(dmp)]2+

2bitpy + Cu(ClO4)2.6H2O → [Cu(bitpy)]2+

bitpy + Cu(NO3)2.3H2O + bpy → [Cu(terpy)(bpy)]2+

bitpy + Cu(NO3)2.3H2O → [Cu(bitpy)(NO3)]+

2imthma + Cu(ClO4)2.6H2O → [Cu(imthma)]2+

2bzthma + Cu(NO3)2.3H2O → [Cu(bzthma)(NO3)]2+

2pythma + Cu(NO3)2.3H2O → [Cu(pythma)(NO3)]2+

Synthesis of Copper(II) Complexes

15

rt

Δ

rt

rt

(1-3)

(4)

(5)

(6)

(7)

(8)

(9)

Δ

Δ

Δ

Chapter 3

Interaction of Mixed Ligand

Copper(II) Complexes with DNA and

its Anti-proliferative Effects

16

Synthesis of Mixed Ligand Copper(II)

Complexes

[Cu(itpy)(dmp)]2+

(1)

[Cu(ptpy)(dmp)]2+

(2)

[Cu(meotpy)(dmp)]2+

(3)

17

Complex UV-Visible Spectroscopy

λmax (nm)

ESI-MS

(m/z)

FT-IR

cm-1

1 218, 275, 343, 591-645 285.34 3396, 2926,

1618, 1384,

1029, 794

2 212, 276, 350, 580-640

291.34 3395, 3024,

1595, 1384,

1337, 856

3 218, 277, 343, 595-680

305.20 3399, 2918,

1599, 1384,

1017, 837

Characterization of Cu(II) Complexes

18

ORTEP

representation:

Distorted square

pyramidal (4+1)

X-ray Diffraction of [Cu(itpy)(dmp)](NO3)2

Complex Bond distance/Å

Cu(1) - N(12) 1.931(2)

Cu(1) - N(42) 1.980(2)

Cu(1) - N(1) 2.037(2)

Cu(1) - N(18) 2.053(2)

Cu(1) - N(31) 2.219(2)

19

2.219 (2) Å from dmp ligand

Jahn Teller Distortion

τ = 0.33

Basal plane from itpy and

one from dmp

ORTEP representation:

Between trigonal

bipyramidal and square

pyramidal


Cu(1)-N(12) 1.926(2)

Cu(1)-N(18) 2.013(2)

Cu(1)-N(1) 2.032(2)

Cu(1)-N(42) 2.067(2)

Cu(1)-N(31) 2.114(2)

X-ray Diffraction of [Cu(ptpy)(dmp)](NO3)2

20

τ = 0.63

Cu-N(eq) ≈ Cu-N(ax)

Sq pyramidal trigonal bipyramidal

Basal plane from both N of dmp ligand

and from terpy ligand

X-ray Diffraction of [Cu(meotpy)(dmp)](NO3)2

21

ORTEP representation:

Distorted trigonal

bipyramidal (3+2)


Cu(1)-N(12) 1.935(2)

Cu(1)-N(42) 1.994(2)

Cu(1)-N(1) 2.035(2)

Cu(1)-N(18) 2.048(2)

Cu(1)-N(31) 2.222(2)

τ = 0.89

2Cu(ax) bond distances are 2.03 &

2.04Å by terpy ligand

Cu-N(31) Jahn Teller distortion

Basal plane from dmp ligand and

one from terpy ligand

Liquid Nitrogen Temperature

Cu(II) complexes in DMSO

Complex 1 gǁ : 2.22; g┴ : 2.05

Complex 2 gǁ : 2.22; g┴ : 2.04

Complex 3 gǁ : 2.22; g┴ : 2.06

gǁ > g┴

EPR of Complexes 1-3

22

DNA Binding and Cleavage Studies

23

Electronic Absorption Studies

Complex 1

Kb = 3.35 (±0.32) × 105 M-1

Both complexes are groove binders – Increase in absorbance

with increase in the concentration of complexes

24

Complex 2

Kb = 2.37 (±0.21) × 105 M-1


Intercalative mode of binding – Decrease in absorbance with

increase in the concentration of complex 25

Complex 3

Kb = 7.10 (±0.25) × 104 M-1

Viscosity Measurements

Effect of complexes 1, 2 and 3 (0–200 µM) on the viscosity

of CT-DNA (200 µM)

Complex 1 & 2– Random changes - Groove binders

Complex 3 - Linear increase - Intercalator 26

Gel Electrophoretic Mobility Assay

1 2 3 4 5 6

Complex 1

Form II

Form III

Form I

Complexes 1 & 2 in the presence of minor groove binder

Lane 1 : DNA alone

Lane 2 : DNA + 10 µM Complex 1





Lane 1 : DNA alone

Lane 2 : DNA + H2O2

Lane 3 : DNA + 10 µM Complex 2 + H2O2



Lane 1 : DNA + 2 µl DMSO

Lane 2 : DNA + 2 µl Distamycin (Dist)

Lane 3 : DNA + 20 µM Complex 1 + 2 µl Dist

Lane 4 : DNA + H2O2 + 20 µM Complex 2 + 2 µl Dist

Lane 5 : DNA + H2O2 + 20 µM Complex 2 + 2 µl DMSO

27

Complex 2

1 2 3 4 5

Form II

Form III

Form I

1 2 3 4 5

Form II

Form III

Form I

Gel Electrophoretic Mobility Assay-

Complex 3

Form II

Form I

1 2 3 4 5 6

Lane 1 : DNA alone






Complex 1 & 3 – Hydrolytic cleavage

Complex 2 – Oxidative cleavage

Complex 1 – Minor groove binder

Complex 2 – Major groove binder

28

Anti-proliferative Studies

Complex IC50 Values (µM)

NIH3T3 MG63

1 0.50 0.125

2 0.81 0.78

3 1.50 0.75

29

Complex

2

Phase Contrast and Fluorescence Image

30

• Complexes 1 & 3 at 0.125 and 0.75 µM

• Both morphological changes and Annexin V & PI staining shows

apoptotic cell death

Caspase 3 and 9 Activities

• NIH3T3 - no significant differences in cas -3 and -9 activities

• MG63 - Complexes 1 & 3 showed two fold increase in Cas-3

activity 31

All the complexes are mixed ligands with five coordination geometry

Imidazole and pyridyl possessing terpyridyl groups containing

complexes shows minor and major groove binding aptitude towards

DNA whereas methoxybenzyl terpyridyl complex possesses

intercalation

Imidazole and methoxybenzyl terpyridine showed hydrolytic cleavage

whereas pyridylterpyridine underwent oxidative cleavage

To rationalize among groove binders the minor groove has greater

antiproliferative effects on cancerous cells

Amongst groove binders and intercalators, imidazolylterpyridine minor

groove binder showed greater selectivity and low IC50 on cancerous

cells

Salient Features

32

DNA Condensation Ability of

benzimidazolylterpyridine

Copper(II) Complexes and its Anti-

proliferative Effects

Chapter 4

33

Synthesis of Varying Coordination of

Copper(II) Complexes

34

[Cu(bitpy)(phen)]2+

(5)

[Cu(bitpy)(NO3)2]2+

(6)

[Cu(bitpy)2]2+

(4)

2+

2+ 2+


λmax (nm)

FT-IR

cm-1

4 270, 287, 354, 580-680 3069, 1613, 1548, 1472,

1089, 792, 625

5 270, 350, 580-660

3367, 3188, 1665, 1614,

1384, 849, 720

6 288, 355, 680-730

3069, 1613, 1548, 1472,

1089, 792

Characterization of Complexes

35

ESI-MS of [Cu(bitpy)2]2+

36

Base peak as molecular ion peak

[Cu(bitpy)2]2+

Complex ion pair

[Cu(bitpy)2]+.ClO4

ESI-MS of [Cu(bitpy)(phen)](NO3)2

37

[Cu(bitpy)(phen)]2+

[[Cu(bitpy)] 2+NO3]+

[Cu(bitpy)(phen)]2+NO3

ESI-MS of [Cu(bitpy)(NO3)2]+

38

[Cu(bitpy)(NO3)]+

[Cu(bitpy)(CH3CN)]2+

EPR Spectrum of Complexes 4-6

39

Liquid Nitrogen Temperature

Cu(II) complexes in DMSO

Complex 4 gǁ : 2.22; g┴ : 2.05

Complex 5 gǁ : 2.22; g┴ : 2.04

Complex 6 gǁ : 2.22; g┴ : 2.06

gǁ > g┴

DNA Binding and Condensation

Studies

40

Complex 4 Kb = 1.84 (± 0.32) X 104 M-1

Complex 5 Kb = 1.83 (± 0.57) X 104 M-1

Complex 6 Kb = 1.87 (± 0.21) X 104 M-1


41

Intercalation - Almost similar

binding efficacy of all the three

complexes due to bitpy ligand

Viscosity Measurements

Linear increase confirming intercalative mode of binding of

three complexes to DNA 42

Circular Dichroic Spectral Analysis

Complex 4 shows greater changes in the helicity and 7 nm red-

shift

Complex 5 shows relatively less changes in the helicity whereas

base stacking has been blue-shifted to 7-9 nm

43

Circular Dichroic Spectral Analysis

CD bands Positive band Negative band

[Cu(bitpy)2](ClO4)2 (4) 4 nm (red-shift) 4 nm (red-shift)

[Cu(bitpy)(phen)](NO3)2 (5) 7 nm (blue-shift) 2 nm (red-shift)

[Cu(bitpy)(NO3)]NO3 (6) 3 nm (red-shift) 4 nm (red-shift)

Complex 6 shows greater

changes in the helicity and 3

nm red-shift

44

Electrophoretic Mobility Assay

Complex 4 Complex 5 Complex 6

Lane 1 : DNA alone

Lane 2 : DNA + 10 µM - 4

Lane 3 : DNA + 20 µM - 4

Lane 4 : DNA + 30 µM - 4

Lane 5 : DNA + 40 µM - 4

Lane 6 : DNA + 50 µM - 4

Lane 7 : DNA + 60 µM - 4

Lane 1 : DNA + 5 µM - 5

Lane 2 : DNA + 10 µM - 5

Lane 3 : DNA + 20 µM - 5

Lane 4 : DNA + 30 µM - 5

Lane 5 : DNA + 40 µM - 5

Lane 6 : DNA + 50 µM - 5

Lane 7 : DNA + 60 µM - 5

Lane 1 : DNA alone

Lane 2 : DNA + 10 µM - 6

Lane 3 : DNA + 20 µM - 6

Lane 4 : DNA + 30 µM - 6

Lane 5 : DNA + 40 µM - 6

Lane 6 : DNA + 50 µM - 6

Lane 7 : DNA + 60 µM - 6

Complex 4 brings about cleavage at low concentration

Complex 5 shows complete condensation since 5 – 60 µM

Complex 6 shows both condensation and hydrolytic cleavage 45

Anti-proliferative Studies


NIH3T3 MG63

4 60.0 1.0

5 5.0 1.2

6 1.0 1.0

46

Complex

6

Morphological Changes- Phase Contrast

Images

47

10µm

10µm

(a) Cell Shrinkage and chromatin condensation

(b) Membrane blebbing observed in MG63 cell line

(a) (a) (b) • Complexes at IC50 concentrations

Annexin V & PI Staining: Caspase 3 and 9

Activities

N1 = Complex 4 at 1.0 µM

N2 = Complex 5 at 1.2 µM

48

NIH3T3 - no significant

differences in cas -3 and -9

activities

MG63 - Complex 4 showed six

fold increase in Cas-3 & -9

activity

10µm 10µm

Six-, Five- and Four coordinated complexes with

benzimidazole head groups have been synthesized

4 ~ 5 ~ 6 almost equal binding affinity towards CT-DNA

DNA condensation of complexes follows the order: 4 > 5 > 6

The anti-proliferative effects of the complexes are 4 > 5 whose

IC50 values are relatively lower and showed greater selectivity

towards MG63 cells

Salient Features

The cell death occurs

via apoptosis and it is

by mitochondrial

mediated pathway

which have been

proved by caspase

activity

49

Investigation of Cu(II) Complexes of

Thiophenemethanamine Derivatives

with DNA and their Cytotoxicity Profile

Chapter 5

50

Structure of Thiophenemethanamine

Derivatives of Cu(II) Complexes

51

[Cu(imthma)2]2+

(7)

[Cu(bzthma)2]2+

(8)

[Cu(pythma)2]2+

(9)


λmax (nm)

FT-IR

cm-1

7 208, 440-780 3396, 2926, 1618, 1384,

1029, 794

8 210, 270, 277, 520-790

3395, 3024, 1595, 1384,

1337, 856

9 208, 260, 550-800

3399, 2918, 1599, 1384,

1017, 837

Characterization of Cu(II) Complexes

52

ESI-MS and EPR Spectra of Complex 7

53

Mol. Ion peak

[Cu(imthma)2]2+

gǁ : 2.29

g┴ : 2.07

Aǁ : 149G

Distorted square

planar geometry

54

[Cu(bzthma)2-H]+


gǁ : 2.31

g┴ : 2.08

Aǁ : 149G

Distorted square

planar geometry

55

gǁ : 2.30

g┴ : 2.08

Aǁ : 155G

Distorted square

planar geometry


Mol. Ion peak

[Cu(pythma)2]2+

ORTEP Representation of Complex 7

56


Cu-N(1) 1.942(1)

Cu-N(3) 2.054(1)

Cu-N(1)# 1.942(1)

Cu-N(3)# 2.054(1)

• Uncoordinated sulfur

atom is evident from XRD

• EPR confirmed Square

planar geometry

DNA Binding and Cleavage Studies

57

Competitive Binding Studies

58

Complex 7 Kapp = 10.0 (± 0.23) × 105 M-1

Complex 8 Kapp = 6.30 (± 0.31) × 105 M-1

Complex 9 Kapp = 8.31 (± 0.19) × 105 M-1

Complexes 7-9 show groove

binding ability towards DNA

Fluorescence Spectra of Complexes

59

Complex Stern-Volmer quenching

constant (M-1)

Absence of

DNA

Presence of

DNA

7 4.61 x 103 4.32 x 103

8 2.33 x 103 2.08 x 103

9 3.90 x 103 4.11 x 103

[Fe(CN)6]4- shows groove binding

(a) DNA alone (b) DNA+Complex 7

(c) DNA+Complex 8 (d) DNA+Complex 9

Circular Dichroic Spectral and Viscosity

Measurements

Complexes 7 & 9 showed groove binding

For complex 8 intercalation mode of binding cannot be ruled out 60

Molecular Docking Studies Duplex sequence d(CGCGAATTCGCG)2 PDB NO: 355D

Autodock Vina 1.0


61

Complexes 7 & 9 bind to the grooves of DNA

Complex 8 showed partial intercalation via., major groove

Agarose Gel Electrophoresis: Cleavage of

Complexes in the Presence of H2O2

Form II

Form III

Form I

Lane 1: DNA

Lane 2: DNA+ H2O2

Lane 3: DNA + 10μM - 7 + H2O2

Lane 4: DNA + 20μM - 7 + H2O2

Lane 5: DNA + 30μM - 7 + H2O2

Lane 1: DNA

Lane 2: DNA+ H2O2

Lane 3: DNA+ 10μM - 8 + H2O2

Lane 4: DNA+ 20μM - 8 + H2O2

Lane 5: DNA+ 30μM - 8 + H2O2

Lane 6: DNA+ 40μM - 8 + H2O2

Lane 1: DNA

Lane 2: DNA+ H2O2

Lane 3: DNA+ 10μM - 9 + H2O2

Lane 4: DNA+ 20μM - 9 + H2O2

Lane 5: DNA+ 30μM - 9 + H2O2

Lane 6: DNA+ 40μM - 9 + H2O2

Lane 7: DNA+ 50μM - 9 + H2O2


62

All the complexes showed oxidative cleavage in the

presence of hydrogen peroxide

1 2 3 4 5 1 2 3 4 5 6 1 2 3 4 5 6 7

Anti-Proliferative Studies


NIH3T3 MG63

7 5.0 5.0

8 40.0 4.0

9 40.0 7.5

63

Complex

7

Morphological Changes- Phase Contrast

Images

64

(a) (b)

Complexes at IC50 concentration

(a) Membrane blebbing

(b) Cell Shrinkage and chromatin condensation observed

in MG63 cell line

10µm

Morphological Changes- Annexin V & PI

65

MG63

Cells

NIH3T3

Cells

10µm

10µm

Red Orange stain indicating apoptotic cell death induced by

complexes 8 and 9

Caspase Activities

66

Complex 8 - benzimidazolyl derivative showed significant

increase in caspase activities compared to normal cells

Three copper(II) complex of thiophenemethylamine derivatives

have been synthesized and characterized

Complexes 7 & 9 possess groove binding whereas 8 possess

partial intercalation ability to CT-DNA in the binding order of

105

Gel electrophoresis shows complexes possess nuclease

activity in the presence of peroxide. The cleavage efficiency is

in the order: complex 7>8~9

Salient Features

Anti-proliferative effects on

MG-63 cells follows

benzimidazolyl > pyridyl >

imidazolyl

Apoptotic cell death and the

mitochondrial mechanistic

pathway has been proved 67

Summary and Conclusion

Chapter 6

68

Complexes 1-3 are five coordinate complexes with varying

substituent at 4’ position of terpyridine (imidazole, pyridyl

and methoxybenzyl moieties) and co-ligand is dmp

Complex 1 and 2 possess groove binding ability with DNA

whereas complex 3 binds intercalatively

Complex 1 is a minor groove binder, complex 2 is a major

groove binder which are evident from electrophoretic mobility

assay in the presence of distamycin

Complexes 1 & 3 cleaves DNA hydrolytically whereas

complex 2 cleaves oxidatively cleavage

Anti-proliferative studies reveals that complex 1 and 3

showed selectivity for cancerous cells whereas 2 is not


69

70

Complexes 1 & 3 showed 4 & 2-fold selectivity on cancerous

cell (125 nM and 750 nM) than normal (500 nM and 1500 nM),

respectively


[Cu(itpy)(dmp)]2+ (1) [Cu(ptpy)(dmp)]2+(2) [Cu(meotpy)(dmp)]2+(3)

Complex 1 – minor groove binder – hydrolytic cleavage – 4-fold

cytotoxic effect on cancerous cells than normal cells

71

Complexes 4-6, retaining the benzimidazolylterpyridine as a

common tridentate ligand in Cu(II) complexes with varying

coordination geometries

Complexes 4-6 bind to DNA intercalatively with equal binding

affinity (1.1 X 105 mol-1)

Complexes 4 and 5 showed DNA condensing ability at a

concentration of 10 and 5 µM, respectively whereas complex 6

cleaves DNA hydrolytically in addition to DNA condensation

Complexes 4 and 5 showed specificity on cancerous cells

whereas complex 6 is not

Amongst, complex 4 at a very low concentration of 1 µM

showed greater cytotoxic effect on MG63 cell line than normal

cell line (60 µM)


Complex 4 – intercalator – DNA condensing agent – 60-fold greater

anti-proliferative effect than normal cells


[Cu(bitpy)(phen)]2+

(5)

[Cu(bitpy)(NO3)2]2+

(6) [Cu(bitpy)2]

2+

(4)

Complexes 7-9 are thiophenemethanamine derivatives of

imidazolyl, benzimidazolyl and pyridyl units

Complex 7 & 9 are groove binders whereas complex 8 binds

with DNA via partial intercalation through major groove

confirmed using molecular docking studies

All these complexes (7-9) cleave DNA oxidatively

Complex 8-9 exhibit against cancerous cells (4 and 7.5 µM,

respectively) than normal cells (40 and 40 µM, respectively)

whereas complex 7 doesn’t

Complexes 8 & 9 show 10 & 5-fold selectivity on cancerous cell

than normal cell line


74

Complex 8 – groove binder – oxidative cleavage – 10-fold higher

cytotoxic effects on cancerous cell line than normal cell line


[Cu(imthma)2]2+

(7)

[Cu(bzthma)2]2+

(8)

[Cu(pythma)2]2+

(9)

75

[Cu(bitpy)2]2+ > [Cu(bzthma)2]

2+ > [Cu(itpy)(dmp)]2+

(4) (8) (1)


List of Publications Anomalous behavior of pentacoordinate copper complexes of

dimethylphenanthroline and derivatives of terpyridine ligands: Studies on DNA

binding, cleavage and apoptotic activity

S. Rajalakshmi, Thomas Weyhermüller, Allen J Freddy, Hannah R Vasanthi,

Balachandran Unni Nair *

European Journal of Medicinal Chemistry 46 (2011) 608-617

Copper (II) complexes possessing derivatives of terpyridine: An underpinning step

towards breast antiproliferative agent

S. Rajalakshmi, Thomas Weyhermüller, Balachandran Unni Nair*

Journal of Inorganic Biochemistry 117 (2012) 48-59

DNA cleavage activity by a mononuclear iron(II)Schiff base complex: Synthesis and

structural characterization

Pal, B. Biswas, M. Mitra, S. Rajalakshmi, C. S. Purohit, S. Hazra, G. S. Kumar,

Balachandran Unni Nair*, Rajarshi Ghosh*

Journal of Chemical Sciences 125 (2013) 1161-1168

76

List of Publications

DNA binding and cleavage activity of a structurally characterized oxobridged diiron(III)

complex

Biswas, M. Mitra, A. Pal, A. Basu, S. Rajalakshmi, P. Mitra, N. Aliaga-Alcalde, G. S.

Kumar, Balachandran Unni Nair *, Rajarshi Ghosh*

Indian Journal of Chemistry Vol. 52A, December (2013) 1576-1583

Investigation of nuclease, protelytic and anti-proliferative effects of copper(II)

complexes of thiophene methyl amine derivatives

S. Rajalakshmi, M S Kiran, V G Vaidyanathan, E R Azhagiya Singam, V

Subramaniam, and Balachandran Unni Nair*

European Journal of Medicinal Chemistry 46 (2013) 608-617

DNA condensing ability of copper(II) complexes and their anti-proliferative effect on

cancerous cell

S. Rajalakshmi, Manikantan Syamala Kiran, Balachandran Unni Nair*

European Journal of Medicinal Chemistry (2014) In Press

77

Acknowledgement

My Mentor

Acknowledgements • Dr. Balachandran Unni Nair • Prof. A B Mandal

• Dr. Aruna Dhatthreyran • Dr. J Raghava Rao

• Dr. V Narayanan • Dr. V Subramanian

• Dr. M S Kiran • Dr K J Sreeram

• Dr. Thomas Weyhermuller • Dr Nishad Fathima

• Prof J Subramanian and CPL • Dr Easwaramoorthy

• Mr. D Muralidharan and CSIL • Dr. V G Vaidyanathan

• CSIR and DST • Mr. Azhagiya Singam

• SAIF, IIT Madras • Dr. K Sundaravel

• Seniors and Juniors • Dr. Yamini Asthana

Chemical Laboratory • Family and Friends CLRI!! 79

80

Members of Chemical Laboratory

81

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K

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