SYNTHESIS OF TRANSITION METAL COMPLEXES CONTAINING ...

SYNTHESIS OF TRANSITION METAL COMPLEXES CONTAINING

SYMMETRICAL CHALCONE-DERIVED SCHIFF BASES AND CYTOTOXIC STUDIES AGAINST BLADDER CANCER CELLS

NABEEL ARIF TAWFEEQ

FS 2019 60


SYMMETRICAL CHALCONE-DERIVED SCHIFF BASES AND

CYTOTOXIC STUDIES AGAINST BLADDER CANCER CELLS

By

NABEEL ARIF TAWFEEQ

Thesis Submitted to the School of Graduate Studies, Universiti Putra Malaysia,

in Fulfillment of the Requirements for the Degree of Doctor of Philosophy

May 2019

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COPYRIGHT

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unless otherwise stated. Use may be made of any material contained within the thesis

for non-commercial purposes from the copyright holder. Commercial use of material

may only be made with the express, prior, written permission of Universiti Putra

Malaysia.

Copyright © Universiti Putra Malaysia

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Abstract of thesis presented to the Senate of Universiti Putra Malaysia in fulfillment

of the requirement for the degree of Doctor of Philosophy


SYMMETRICAL CHALCONE-DERIVED SCHIFF BASES AND

CYTOTOXIC STUDIES AGAINST BLADDER CANCER CELLS

By

NABEEL ARIF TAWFEEQ

May 2019

Chairman : Mohamed Ibrahim Mohamed Tahir, D.Phil.

Faculty : Science

Dithiocarbazate Schiff bases and their derivatives have drawn considerable attention

due to their unique properties and applications. Many dithiocarbazate metal complexes

have been synthesised and applied in many applications such as antibacterial,

antifungal, antioxidant agents and in catalysis. Dithiocarbazate metal complexes have

also shown significant cytotoxicity against many types of cancer cell lines. This study

aims to synthesise non-toxic compounds by synthesising para substituted chalcone

derivatives and studying the effect of substituted functional group electronegativity on

the cytotoxicity of the metal complexes. Nine chalcones were synthesised using base-

catalysed Aldol condensation. The chalcones were symmetrical in order to direct the

electron density towards the transition metal in the complexes. These symmetrical

chalcones were then reacted with S-benzyldithiocarbazate to form nine novel Schiff

bases. A total of 45 novel metal complexes were synthesised by reacting these nine

Schiff bases with five divalent transition metal acetates which were Ni2+, Fe2+, Cu2+,

Zn2+ and Cd2+. These Schiff bases and their metal complexes were fully characterised

using various characterisation techniques including FTIR, UV-Vis, 1H and 13C NMR

spectroscopy, mass spectral, elemental analysis, and single crystal X-ray diffraction.

The cytotoxic properties of these compounds were also tested against two types of

bladder cancer cell lines which were the minimum-invasive human bladder cancer

carcinoma cell line (RT112) and the invasive human bladder carcinoma cell line

(EJ28).All Schiff bases were inactive against both types of bladder cancer cell. The

unsubstituted chalcones and their metal complexes were inactive against both cells

which means the substituted group on benzene ring plays an important roles toward

the cytotoxicity of metal complexes. Cu(II) complexes of DTASB, DEASB, DIPASB,

DCLASB, DBRASB, DNNMASB and DMeOSB showed moderate cytotoxicity

against both cell lines with more selectivity toward EJ-28 than RT-112. Less than that,

Zn(II) complexes of DTASB, DEASB and DIPASB showed moderate activity against

bladder cancer cell line type EJ-28 while they were inactive against RT-112 cell lines.

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An Fe(II) complex, FeDMeOSB, showed moderate activity against both cell lines.

CuDMeOSB showed highest cytotoxicity against both types of bladder cancer cell

lines EJ-28 and RT-112 with IC50 values equal to 1.651 and 1.762 M, respectively.

In addition, CuDNNMASB showed more selectivity against RT-112 than EJ-28 with

IC50 value equal to 1.874 M.

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Abstrak tesis yang dikemukakan kepada Senat Universiti Putra Malaysia sebagai

memenuhi keperluan untuk ijazah Doktor Falsafah

SINTESIS KOMPLEKS LOGAM PERALIHAN MENGANDUNGI BES

SCHIFF TERBITAN KALKON BERSIMETRI DAN KAJIAN SITOTOKSIK

TERHADAP SEL KANSER PUNDI

Oleh

NABEEL ARIF TAWFEEQ

Mei 2019

Penggerusi : Mohamed Ibrahim Mohamed Tahir, D.Phil.

Fakulti : Sains

Bes Schiff ditiokarbazat dan terbitannya telah mendapat perhatian yang besar

disebabkan oleh sifat dan aplikasi unik mereka. Banyak kompleks logam ditiokarbazat

telah disintesis dan digunakan dalam banyak aplikasi seperti antibakteria, antikulat,

agen antioksidan dan pemangkinan. Kompleks logam ditiokarbazat juga menunjukkan

sitotoksisiti yang ketara terhadap pelbagai jenis sel kanser. Kajian ini bertujuan untuk

mensintesis sebatian bukan toksik dengan mensintesis terbitan para kalkon gantian

dan mengkaji kesan keelektronegatifan kumpulan fungsi yang digantikan pada

kesitotoksikan kompleks logam. Sembilan kalkon telah disintesis dengan

menggunakan pemeluwapan Aldol berbes. Kalkon ini kemudiannya bertindak balas

dengan S-benzilditiokarbazat untuk membentuk sembilan novel bes Schiff. Empat

puluh lima kompleks logam novel telah disintesis dengan bertindak balas terhadap

sembilan bes Schiff dengan lima asetat logam peralihan divalen iaitu Ni2+, Fe2+, Cu2+,

Zn2+ dan Cd2+. Bes Schiff dan kompleks logam mereka telah dicirikan sepenuhnya

menggunakan teknik pencirian pelbagai termasuk spektroskopi FTIR, UV-Vis, 1H & 13C NMR, spektrum jisim, analisis unsur, dan pembelauan sinar-X hablur tunggal.

Sifat sitotoksik sebatian ini juga diuji terhadap dua jenis sel kanser pundi iaitu sel

karsinoma kanser pundi manusia yang kurang invasif (RT112) dan sel karsinoma

kanser pundi manusia yang invasif (EJ28). Semua bes Schiff tidak aktif terhadap

kedua-dua jenis sel kanser pundi. Kalkon yang tiada gantian dan kompleks logam

mereka tidak aktif terhadap kedua-dua sel bermaksud kumpulan yang digantikan pada

gelang benzena memainkan peranan penting ke arah kesitotoksikan kompleks logam.

Kompleks Cu(II) dengan DTASB, DEASB, DIPASB, DCLASB, DBRASB,

DNNMASB dan DMeOSB menunjukkan kesitotoksikan sederhana terhadap kedua-

dua sel sel dengan lebih selektif ke arah EJ-28 daripada RT-112. Kompleks Zn(II)

dengan DTASB, DEASB dan DIPASB menunjukkan aktiviti sederhana terhadap jenis

sel kanser pundi jenis EJ-28 sementara mereka tidak aktif terhadap sel RT-112.

Kompleks Fe(II), FeDMeOSB, menunjukkan aktiviti sederhana terhadap kedua-dua

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sel. CuDMeOSB menunjukkan kesitotoksikan tertinggi terhadap kedua-dua jenis sel

kanser pundi EJ-28 dan RT-112 dengan nilai IC50 bersamaan dengan 1.651 dan 1.762

M masing-masing. Di samping itu, CuDNNMASB menunjukkan lebih banyak

kepilihan terhadap RT-112 daripada EJ-28 dengan nilai IC50 bersamaan dengan 1.874

M.

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ACKNOWLEDGEMENTS

First and foremost, I would like to acknowledge and thank my project supervisor, Dr

Mohamed Ibrahim Mohamed Tahir, for his supporting, patience, wisdom,

encouragements and invaluable guidance during my PhD study. I will forever

remember those long talks we had in both academic and personal matters. I would also

like to thank Assoc. Prof. Dr Thahira Begum, who has also been there for her advice,

encouragement, friendship and guidance. I am also grateful to Assoc. Prof. Dr

Abhimanyu for his advice, guidance and using his lab for doing cytotoxicity part in

this project. Also I would like to thank Dr Mohd Farid for his guidance and advice.

Special thanks to Prof. Karen A. Crouse for her advice, supporting and motivation. I

am also indebted to all lecturers, the laboratory thechnicians and staff in the Faculty

of Science and Faculty of Medicine for helping me throughout my PhD study.

I would like to thank my dear labmates: Nadia Enis, Fatiha, Fadila, Chah Chee Keong,

Lee Chin, Ali, Idris, Nabihah and Nazirah. We have had a lot of sweet memories

together.

Last but not least, I gratefully thank my wife Iqbal and my sons Farooq, Husham,

Ahmed and my daughter Haneen for their encouragements, supporting and

unconditional love. Special thanks to my father, mother. Also I would like to thank

my brothers Kamal, Waleed, Tagreed and Waiel.

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This thesis was submitted to the Senate of Universiti Putra Malaysia and has been

accepted as fulfilment of the requirements for the degree of Doctor of Philosophy. The

members of the Supervisory Committee were as follows:

Mohamed Tahir Mohamed Ibrahim, D. Phil.

Senior Lecturer

Faculty of Science

Universiti Putra Malaysia

(Chairman)

Thahira Begum, PhD

Associate Professor

Faculty of Science


(Member)

Mohd Farid Ismail, PhD

Senior Lecturer

Faculty of Science


(Member)

Abhimanyu Veerakumarasivam, PhD

Professor

Department of Biological Sciences, School of Science and Technology

Sunway University

(Member)

_________________________

ROBIAH BINTI YUNIS, PhD

Professor and Dean

School and Graduate Studies


Date:

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Declaration by graduate student

I hereby confirm that:

this thesis is my original work;

quotations, illustrations and citations have been duly referenced;

this thesis has not been submitted previously or concurrently for any other degree

at any other institutions;

intellectual property from the thesis and copyright of thesis are fully-owned by

Universiti Putra Malaysia, as according to the Universiti Putra Malaysia

(Research) Rules 2012;

written permission must be obtained from supervisor and the office of Deputy

Vice Chancellor (research and Innovation) before thesis is published (in the form

of written, printed or in electronic form) including books, journals, modules,

proceedings, popular writings, seminar papers, manuscripts, posters, reports,

lecture notes, learning modules or any other materials as stated in the Universiti

Putra Malaysia (Research) Rules 2012;

there is no plagiarism or data falsification/fabrication in the thesis, and scholarly

integrity is upheld as according to the Universiti Putra Malaysia (Graduate

Studies) Rules 2003 (revision 2012-2013) and the Universiti Putra Malaysia

(Research) Rules 2012. The thesis has undergone plagiarism detection software.

Signature: ________________________ Date: _______________

Name and Matric No.: Nabeel Arif Tawfeeq, GS42850

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Declaration by Members of Supervisory Committee

This is to confirm that:

the research conducted and the writing of this thesis was under our supervision;

supervision responsibilities as stated in the Universiti Putra Malaysia (Graduate

Studies) Rules 2003 (Revision 2012-2013) are adhered to.

Signature:

Name of Chairman

of Supervisory

Committee:

Dr. Mohamed Tahir Mohamed Ibrahim

Signature:

Name of Member

of Supervisory

Committee:

Associate Professor Dr. Thahira Begum

Signature:

Name of Member

of Supervisory

Committee:

Dr. Mohd Farid Ismail

Signature:

Name of Member

of Supervisory

Committee:

Professor Dr. Abhimanyu Veerakumarasivam

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TABLE OF CONTENTS

Page

ABSTRACT i

ABSTRAK iii

ACKNOWLEDGEMENTS v

APPROVAL vi DECLARATION viii

LIST OF TABLES xii

LIST OF FIGURES xiv

LIST OF APPENDICES xviii

LIST OF ABBREVIATIONS xxix

CHAPTER

1 INTRODUCTION 1 1.1 General 1 1.2 Dibenzalacetone Ketones 3 1.3 Dithiocarbazate 6 1.4 Schiff bases 7 1.5 Metal complexes 8 1.6 Cytotoxicity 10 1.7 Problem statements 10 1.8 Objectives 11

2 LITERATURE REVIEW 12 2.1 Chalcones 12

2.2 Dithiocarbazate 13 2.3 S-substituted dithiocarbazate Schiff bases 15 2.4 Biological activity of dithiocarbazate Schiff bases and their

metal complexes 18 2.5 Chlacone dithiocarbazate Schiff bases 19 2.6 The advantages of using metal complexes as anticancer drug 24 2.7 Selection of transition metals 28

2.7.1 Nickel 28

2.7.2 Copper 29 2.7.3 Cadmium 29 2.7.4 Zinc 29

2.7.5 Iron 30

3 MATERIALS AND METHODS 31

3.1 Chemicals 31

3.2 Preparation of S-benzyldithiocarbazate (SBDTC) 31 3.3 Preparation of Ketones 32

3.3.1 Preparation of Dicinnamalacetone (1E,3E,6E,8E)-1,9-

diphenylnona-1,3,6,8-tetraen-5-one) 32

3.3.2 Preparation of Dibenzalacetone (1E,4E)-1,5-

diphenylpenta-1,4-dien-3-one 32

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3.4 Preparation of Schiff Bases 33

3.5 Preparation of Metal Complexes 34 3.6 Physico-chemical Measurements, Elemental and Spectral

Analysis 35 3.6.1 Melting Point Measurements 35 3.6.2 CHNS Analysis 35 3.6.3 Transition Metal Analysis 36 3.6.4 Conductivity Measurements 36 3.6.5 Magnetic Susceptibility Measurements 36 3.6.6 Fourier Transformer Infrared (FTIR)

Spectrophotometric Analysis 36 3.6.7 Ultraviolet-Visible Spectrophotometric Analysis 36 3.6.8 Nuclear Magnetic Resonance Analysis (1H&13C-

NMR) 37

3.6.9 Mass Spectroscopic Analysis 37 3.7 Structure Determination 37 3.8 Cytotoxic Assay 37

4 RESULTS AND DISCUSSION 39 4.1 Physical Properties 39 4.2 Elemental Analysis 41 4.3 FT-IR Spectroscopy Analysis (Fourier Transform Infrared) 43 4.4 Nuclear Magnetic Resonance Spectroscopic Analysis (NMR) 47 4.5 Mass Spectra Analysis (MS-Spectroscopy) 53 4.6 Molar Conductivity and Magnetic Moment 58 4.7 Ultraviolet-visible spectrophotometric analysis 61 4.8 Crystal Structure analysis 66

4.8.1 Ketones 66

4.8.2 Schiff Base Ligands 69 4.8.3 Transition Metal Complexes 70

4.8.3.1 NiDCLASB Metal Complex 70

4.8.3.2 NiDTASB Metal Complex 71 4.8.3.3 NiDEASB Metal Complex 74

4.8.3.4 CdDEASB Metal Complex 75 4.8.3.5 ZnDBRASB Metal Complex 77

4.8.3.6 ZnDCLASB Metal Complex 79 4.8.3.7 ZnDEASB Metal Complex 80 4.8.3.8 ZnDIPASB Metal Complex 82

4.9 Cytotoxic Assay 84

5 CONCLUSION 89 5.1 Summary 89

5.2 Conclusion 90 5.3 Limitations and Recommendations 91

REFERENCES 92 APPENDICES 105

BIODATA OF STUDENT 209 LIST OF PUBLICATIONS 210

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LIST OF TABLES

Table Page

1.1 Dibenzalacetone derivatives used in this study 4

1.2 The synthesised transition metal complexes 9

2.1 The publication of dithiocarbazate derivatives 15

3.1 Yields and melting points of synthesised ketones 33

3.2 Physical properties, yields and melting points of synthesised Schiff

bases 34

3.3 Colours, yields and melting points of synthesised metal complexes 34

4.1 Physical properties of the synthesized compounds 40

4.2 The elemental analysis data of SBDTC, ketones, Schiff bases and their

transition metal complexes 41

4.3 Selected infrared bands of SBDTC, chalcones, and their Schiff bases 44

4.4 Selected infrared bands of Schiff bases and their metal complexes 46

4.5 1H NMR data of the synthesised ketones 49

4.6 13C NMR data of the synthesised ketones 50

4.7 1H NMR data of the synthesised Schiff bases 50

4.8 13C NMR data of the synthesised Schiff bases 50

4.9 The theoretical and experimental values of the synthesised Schiff bases

base peaks 58

4.10 Molar conductance and magnetic moment of the metal complexes 59

4.11 UV-Vis data for SBDTC, ketones, Schiff bases and their transition

metal complexes 63

4.12 Selected Bond Angles () and Bond Lengths (Å) for DTA 67

4.13 Selected Bond Angles () and Bond Lengths (Å) for DBRA 68

4.14 Selected Bond Angles () and Bond Lengths (Å) for DMeO 68

4.15 Selected Bond Angles () and Bond Lengths (Å) for DMeOSB 69

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4.16 Selected Bond Angles () and Bond Lengths (Å) for NiDCLASB 70

4.17 Selected Bond Angles () and Bond Lengths (Å) for NiDTASB 73

4.18 Selected Bond Angles () and Bond Lengths (Å) for NiDEASB 75

4.19 Selected Bond Angles () and Bond Lengths (Å) for CdDEASB 76

4.20 Selected Bond Angles () and Bond Lengths (Å) for ZnDBRASB 78

4.21 Selected Bond Angles () and Bond Lengths (Å) for ZnDCLASB 79

4.22 Selected Bond Angles () and Bond Lengths (Å) for ZnDEASB 81

4.23 Selected Bond Angles () and Bond Lengths (Å) for ZnDIPASB 83

4.24 Cytotoxic activity of the active compounds against both types of

bladder cancer cell lines EJ-28 and RT-112 87

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LIST OF FIGURES

Figure Page

1.1 General chemical structure of dibenzalacetone 3

1.2 Base catalyzed Aldol condensation mechanism 5

1.3 Chemical structure of dicinnamalacetone DCNMA 5

1.4 Molecular structure of (a) semicarbazide, (b) carbazate, (c)

thiosemicarbazide and (d) dithiocarbazate 6

1.5 Chemical structure of Schiff base 7

1.6 Thione-Thiol tautomerism 7

1.7 Reaction scheme of Schiff bases synthesis and chemical structure of

the synthesized Schiff bases 8

1.8 General chemical structure of the transition metal complexes 9

2.1 ORTEP diagram of di-p-fluorobenzalacetone with 50% probability

displacement elliposeds 12

2.2 ORTEP diagram of di-p-tolualacetone with 50% probability


2.3 Various derivatives of dithiocarbazate 14

2.4 Different aromatic carbonyl compounds used to prepare

dithiocarbazate Schiff bases 16

2.5 Different heterocyclic carbonyl compounds used to prepare

dithiocarbazate Schiff bases 16

2.6 Different ferrocene derivatives used to prepare dithiocarbazate Schiff

bases 17

2.7 Different phosphorous compounds used to prepare dithiocarbazate

Schiff bases 17

2.8 Different chiral compounds used to prepare dithiocarbazate Schiff

bases 18

2.9 Organophosphorus Chalcones Schiff bases with SBDT and

thiosemicarnbazide 21

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2.10 Ferrocene-based chalcones synthesis route 22

2.11 Ferrocene-based chalcones SBDTC Schiff bases synthesis route 22

2.12 Structure Ferrocene-chalcone SBDTC metal complexes 23

2.13 Chemical structure of chalcone and phenylbutanone 23

2.14 ORTEP diagram of Zn(II) complex derived from S-4-

methylbenzyldithiocarbazate and furaldehyde with 50% probability


2.15 ORTEP diagram of Cd(II) complex derived from S-4-

methylbenzyldithiocarbazate and furaldehyde with 50% probability


2.16 ORTEP diagram of Cu(II) complex derived from S-

hexyldithiocarbazate and 4-methoxybenzaldehyde with 50%

probability displacement elliposeds 26

2.17 ORTEP diagram of Ni(II) complex derived from S-

cyclohexyldithiocarbazate and 4-methoxybenzaldehyde with 50%

probability displacement elliposeds (Begum et al., 2017) 27

2.18 ORTEP diagram of Cu(II) complex derived from S-

benzyldithiocarbazate and 2,4,5-trimethoxybenzaldehyde with 50%

probability displacement elliposeds (Islam et al., 2016) 28

3.1 Reaction scheme for synthesis of chalcones, Schiff bases and their

metal complexes 33

4.1 FT-IR spectra of SBDTC, DBA and DBASB 43

4.2 FT-IR spectra of DBASB Schiff Base and its Fe(II) metal complex 45

4.3 1H NMR spectrum of DBA in deuterated methanol 47

4.4 1H NMR spectrum of DBASB in deuterated methanol 48

4.5 13C NMR spectrum of DBA in deuterated methanol 48

4.6 13C NMR spectrum of DBASB in deuterated methanol 49

4.7 1H NMR spectrum of SBDTC in deuterated chloroform 52

4.8 13C NMR spectrum of SBDTC in deuterated chloroform 53

4.9 The Main Mass Fragments for DBASB 54

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4.10 The Main Mass Fragments for DCNMASB 54

4.11 The Main Mass Fragments for DTASB 55

4.12 The Main Mass Fragments for DEASB 55

4.13 The Main Mass Fragments for DIPASB 56

4.14 The Main Mass Fragments for DCLASB 56

4.15 The Main Mass Fragments for DBRASB 57

4.16 The Main Mass Fragments for DMeOSB 57

4.17 The Main Mass Fragments for DNNMASB 58

4.18 UV-Vis spectrum for SBDTC dissolved in acetonitrile 61

4.19 UV-Vis spectrum for DBA dissolved in acetonitrile 62

4.20 UV-Vis spectrum for DBASB dissolved in acetonitrile 62

4.21 UV-Vis spectrum for NiDBASB dissolved in acetonitrile 63

4.22 ORTEP Diagram of DTA where the hydrogen atoms are hidden 67

4.23 ORTEP Diagram of DBRA where the hydrogen atoms are hidden 67

4.24 ORTEP Diagram of DMeO where the hydrogen atoms are hidden 68

4.25 ORTEP Diagram of DMeOSB where the hydrogen atoms are hidden 69

4.26 ORTEP Diagram of NiDCLASB where the hydrogen atoms are

hidden 71

4.27 ORTEP Diagram of NiDTASB where the hydrogen atoms are hidden 72

4.28 ORTEP Diagram of NiDEASB where the hydrogen atoms are hidden 74

4.29 ORTEP Diagram of CdDEASB where the hydrogen atoms are hidden 76

4.30 ORTEP Diagram of ZnDBRASB where the hydrogen atoms are

hidden 77

4.31 ORTEP Diagram of ZnDCLASB where the hydrogen atoms are

hidden 79

4.32 ORTEP Diagram of ZnDEASB where the hydrogen atoms are hidden 81

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4.33 ORTEP Diagram of ZnDIPASB where the hydrogen atoms are

hidden 83

4.34 Pre-screening bar chart for DBASB and its metal complexes against

bladder cancer cell line type RT-112 85

4.35 Pre-screening bar chart for DNNMASB and its metal complexes

against bladder cancer cell line type RT-112 86

4.36 The percentage of living cells after treatment with different

concentrations of CuDNNMASB complex to determine the IC50 value 86

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LIST OF APPENDICES

Appendix Page

A 1 IR spectrum of SBDTC 105

A 2 IR spectrum of DBA 105

A 3 IR spectrum of DBASB 106

A 4 IR spectrum of NiDBASB 106

A 5 IR spectrum of CuDBASB 107

A 6 IR spectrum of FeDBASB 107

A 7 IR spectrum of CdDBASB 108

A 8 IR spectrum of ZnDBASB 108

A 9 IR spectrum of DCNMA 109

A 10 IR spectrum of DCNMASB 109

A 11 IR spectrum of NiDCNMA 110

A 12 IR spectrum of CuDCNMA 110

A 13 IR spectrum of FeDCNMA 111

A 14 IR spectrum of CdDCNMA 111

A 15 IR spectrum of ZnDCNMASB 112

A 16 IR spectrum of DTA 112

A 17 IR spectrum of DTASB 113

A 18 IR spectrum of NiDTASB 113

A 19 IR spectrum of CuDTASB 114

A 20 IR spectrum of FeDTASB 114

A 21 IR spectrum of CdDTASB 115

A 22 IR spectrum of ZnDTASB 115

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A 23 IR spectrum of DEA 116

A 24 IR spectrum of DEASB 116

A 25 IR spectrum of NiDEASB 117

A 26 IR spectrum of CuDEASB 117

A 27 IR spectrum of FeDEASB 118

A 28 IR spectrum of CdDEASB 118

A 29 IR spectrum of ZnDEASB 119

A 30 IR spectrum of DIPA 119

A 31 IR spectrum of DIPASB 120

A 32 IR spectrum of NiDIPASB 120

A 33 IR spectrum of CuDIPASB 121

A 34 IR spectrum of FeDIPASB 121

A 35 IR spectrum of CdDIPASB 122

A 36 IR spectrum of ZnDIPASB 122

A 37 IR spectrum of DCLA 123

A 38 IR spectrum of DCLASB 123

A 39 IR spectrum of NiDCLASB 124

A 40 IR spectrum of CuDCLASB 124

A 41 IR spectrum of FeDCLASB 125

A 42 IR spectrum of CdDCLASB 125

A 43 IR spectrum of ZnDCLASB 126

A 44 IR spectrum of DBRA 126

A 45 IR spectrum of DBRASB 127

A 46 IR spectrum of NiDBRASB 127

A 47 IR spectrum of CuDBRASB 128

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A 48 IR spectrum of FeDBRASB 128

A 49 IR spectrum of CdDBRASB 129

A 50 IR spectrum of ZnDBRASB 129

A 51 IR spectrum of DMeO 130

A 52 IR spectrum of DMeOSB 130

A 53 IR spectrum of NiDMeOSB 131

A 54 IR spectrum of CuDMeOSB 131

A 55 IR spectrum of FeDMeOSB 132

A 56 IR spectrum of CdDMeOSB 132

A 57 IR spectrum of ZnDMeOSB 133

A 58 IR spectrum of DNNMA 133

A 59 IR spectrum of DNNMASB 134

A 60 IR spectrum of NiDNNMASB 134

A 61 IR spectrum of CuDNNMASB 135

A 62 IR spectrum of FeDNNMASB 135

A 63 IR spectrum of CdDNNMASB 136

A 64 IR spectrum of ZnDNNMASB 136

B 1 1H NMR Spectrum of SBDTC 137

B 2 13C NMR Spectrum of SBDTC 137

B 3 1H NMR Spectrum of DBA 138

B 4 13C NMR Spectrum of DBA 138

B 5 1H NMR Spectrum of DBASB 139

B 6 13C NMR Spectrum of DBASB 139

B 7 1H NMR Spectrum of DCNMA 140

B 8 13C NMR Spectrum of DCNMA 140

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B 9 1H NMR Spectrum of DCNMASB 141

B 10 13C NMR Spectrum of DCNMASB 141

B 11 1H NMR Spectrum of DTA 142

B 12 13C NMR Spectrum of DTA 142

B 13 1H NMR Spectrum of DTASB 143

B 14 13C NMR Spectrum of DTASB 143

B 15 1H NMR Spectrum of DEA 144

B 16 13C NMR Spectrum of DEA 144

B 17 1H NMR Spectrum of DEASB 145

B 18 13C NMR Spectrum of DEASB 145

B 19 1H NMR Spectrum of DIPA 146

B 20 13C NMR Spectrum of DIPA 146

B 21 1H NMR Spectrum of DIPASB 147

B 22 13C NMR Spectrum of DIPASB 147

B 23 1H NMR Spectrum of DCLA 148

B 24 13C NMR Spectrum of DCLA 148

B 25 1H NMR Spectrum of DCLASB 149

B 26 13C NMR Spectrum of DCLASB 149

B 27 1H NMR Spectrum of DBRA 150

B 28 13C NMR Spectrum of DBRA 150

B 29 1H NMR Spectrum of DBRASB 151

B 30 13C NMR Spectrum of DBRASB 151

B 31 1H NMR Spectrum of DMeO 152

B 32 13C NMR Spectrum of DMeO 152

B 33 1H NMR Spectrum of DMeOSB 153

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B 34 13C NMR Spectrum of DMeOSB 153

B 35 1H NMR Spectrum of DNNMA 154

B 36 13C NMR Spectrum of DNNMA 154

B 37 1H NMR Spectrum of DNNMASB 155

B 38 13C NMR Spectrum of DNNMASB 155

C 1 Mas Spectrum of SBDTC 156

C 2 Mas Spectrum of DBASB 156

C 3 Mass Fragmentation of DBASB 157

C 4 Mas Spectrum of DCNMASB 157

C 5 Mass Fragmentation of DCNMASB 158

C 6 Mas Spectrum of DTASB 158

C 7 Mass Fragmentation of DTASB 159

C 8 Mas Spectrum of DEASB 159

C 9 Mass Fragmentation of DEASB 160

C 10 Mas Spectrum of DIPASB 160

C 11 Mass Fragmentation of DIPASB 161

C 12 Mas Spectrum of DCLASB 161

C 13 Mass Fragmentation of DCLASB 162

C 14 Mas Spectrum of DBRASB 162

C 15 Mass Fragmentation of DBRASB 163

C 16 Mas Spectrum of DMeOSB 163

C 17 Mass Fragmentation of DMeOSB 164

C 18 Mas Spectrum of DNNMASB 164

C 19 Mass Fragmentation of DNNMASB 165

D 1 UV-Vis Spectrum of SBDTC 166

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D 2 UV-Vis Spectrum of DBA 166

D 3 UV-Vis Spectrum of DBASB 166

D 4 UV-Vis Spectrum of NiDBASB 166

D 5 UV-Vis Spectrum of CuDBASB 167

D 6 UV-Vis Spectrum of FeDBASB 167

D 7 UV-Vis Spectrum of CdDBASB 167

D 8 UV-Vis Spectrum of ZnDBASB 167

D 9 UV-Vis Spectrum of DCNMA 168

D 10 UV-Vis Spectrum of DCNMASB 168

D 11 UV-Vis Spectrum of NiDCNMASB 168

D 12 UV-Vis Spectrum of CuDCNMASB 168

D 13 UV-Vis Spectrum of FeDCNMASB 169

D 14 UV-Vis Spectrum of CdDCNMASB 169

D 15 UV-Vis Spectrum of ZnDCNMASB 169

D 16 UV-Vis Spectrum of DTA 169

D 17 UV-Vis Spectrum of DTASB 170

D 18 UV-Vis Spectrum of NiDTASB 170

D 19 UV-Vis Spectrum of CuDTASB 170

D 20 UV-Vis Spectrum of FeDTASB 170

D 21 UV-Vis Spectrum of CdDTASB 171

D 22 UV-Vis Spectrum of ZnDTASB 171

D 23 UV-Vis Spectrum of DEA 171

D 24 UV-Vis Spectrum of DEASB 171

D 25 UV-Vis Spectrum of NiDEASB 172

D 26 UV-Vis Spectrum of CuDEASB 172

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D 27 UV-Vis Spectrum of FeDEASB 172

D 28 UV-Vis Spectrum of CdDEASB 172

D 29 UV-Vis Spectrum of ZnDEASB 173

D 30 UV-Vis Spectrum of DIPA 173

D 31 UV-Vis Spectrum of DIPASB 173

D 32 UV-Vis Spectrum of NiDIPASB 173

D 33 UV-Vis Spectrum of CuDIPASB 174

D 34 UV-Vis Spectrum of FeDIPASB 174

D 35 UV-Vis Spectrum of CdDIPASB 174

D 36 UV-Vis Spectrum of ZnDIPASB 174

D 37 UV-Vis Spectrum of DCLA 175

D 38 UV-Vis Spectrum of CLASB 175

D 39 UV-Vis Spectrum of NiDCLASB 175

D 40 UV-Vis Spectrum of CuDCLASB 175

D 41 UV-Vis Spectrum of FeDCLASB 176

D 42: UV-Vis Spectrum of CdDCLASB 176

D 43 UV-Vis Spectrum of ZnDCLASB 176

D 44 UV-Vis Spectrum of DBRA 176

D 45 UV-Vis Spectrum of DBRASB 177

D 46 UV-Vis Spectrum of NiDBRASB 177

D 47 UV-Vis Spectrum of CuDBRASB 177

D 48 UV-Vis Spectrum of FeDBRASB 177

D 49 UV-Vis Spectrum of CdDBRASB 178

D 50 UV-Vis Spectrum of ZnDBRASB 178

D 51 UV-Vis Spectrum of DMeO 178

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D 52 UV-Vis Spectrum of DMeOSB 178

D 53 UV-Vis Spectrum of NiDMeOSB 179

D 54 UV-Vis Spectrum of CuDMeOSB 179

D 55 UV-Vis Spectrum of FeDMeOSB 179

D 56 UV-Vis Spectrum of CdDMeOSB 179

D 57 UV-Vis Spectrum of ZnDMeOSB 180

D 58 UV-Vis Spectrum of DNNMA 180

D 59 UV-Vis Spectrum of DNNMASB 180

D 60 UV-Vis Spectrum of NiDNNMASB 180

D 61 UV-Vis Spectrum of CuDNNMASB 181

D 62 UV-Vis Spectrum of FeDNNMASB 181

D 63 UV-Vis Spectrum of CdDNNMASB 181

D 64 UV-Vis Spectrum of ZnDNNMASB 181

E 1 Crystal Structure Data for DTA 182

E 2 Crystal Structure Data for DBRA 183

E 3 Crystal Structure Data for DMeO 184

E Crystal Structure Data for DMeOSB 185

E 5 Crystal Structure Data for NiDCLASB 186

E 6 Crystal Structure Data for NiDTASB 187

E 7 Crystal Structure Data for NiDEASB 188

E 8 Crystal Structure Data for CdDEASB 189

E 9 Crystal Structure Data for ZnDBRASB 190

E 10 Crystal Structure Data for ZnDCLASB 191

E 11 Crystal Structure Data for ZnDEASB 192

E 12 Crystal Structure Data for ZnDIPASB 193

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F 1 Pre-screening bar chart for DCNMASB and its metal complexes


F 2 Pre-screening bar chart for DTASB and its metal complexes against


F 3 Pre-screening bar chart for DEASB and its metal complexes against


F 4 Pre-screening bar chart for DIPASB and its metal complexes against


F 5 Pre-screening bar chart for DCLASB and its metal complexes against


F 6 Pre-screening bar chart for DBRASB and its metal complexes against


F 7 Pre-screening bar chart for DMeOSB and its metal complexes against


F 8 Pre-screening bar chart for DNNMASB and its metal complexes


F 9 Pre-screening bar chart for DBASB and its metal complexes against

bladder cancer cell line type EJ-28 198

F 10 Pre-screening bar chart for DCNMASB and its metal complexes

against bladder cancer cell line type EJ-28 198

F 11 Pre-screening bar chart for DTASB and its metal complexes against


F 12 Pre-screening bar chart for DEASB and its metal complexes against


F 13 Pre-screening bar chart for DIPASB and its metal complexes against


F 14 Pre-screening bar chart for DCLASB and its metal complexes against


F 15 Pre-screening bar chart for DBRASB and its metal complexes against


F 16 Pre-screening bar chart for DMeOSB and its metal complexes against


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F 17 Pre-screening bar chart for DNNMASB and its metal complexes

against bladder cancer cell line type EJ-28 202

F 18 The percentage of living (RT-112) cells after treatment with different

concentrations of CuDTASB complex to determine the IC50 value 202

F 19 The percentage of living cells (RT-112) after treatment with different

concentrations of CuDEASB complex to determine the IC50 value 202


concentrations of CuDIPASB complex to determine the IC50 value 203


concentrations of CuDCLASB complex to determine the IC50 value 203


concentrations of CuDBRASB complex to determine the IC50 value 203


concentrations of CuDMeOSB complex to determine the IC50 value 204


concentrations of FeDMeOSB complex to determine the IC50 value 204


concentrations of CuDNNMASB complex to determine the IC50

value 204

F 26 The percentage of living cells (EJ-28) after treatment with different

concentrations of CuDTASB complex to determine the IC50 value 205


concentrations of CuDEASB complex to determine the IC50 value 205


concentrations of CuDIPASB complex to determine the IC50 value 205


concentrations of ZnDTASB complex to determine the IC50 value 206


concentrations of ZnDEASB complex to determine the IC50 value 206


concentrations of CuDCLASB complex to determine the IC50 value 206


concentrations of CuDBRASB complex to determine the IC50 value 207

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concentrations of CuDMeOSB complex to determine the IC50 value 207


concentrations of FeDMeOSB complex to determine the IC50 value 207


concentrations of CuDNNMASB complex to determine the IC50

value 208

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LIST OF ABBREVIATIONS

SBDTC S-benzyldithiocarbazate

DBA Dibenzalacetone

DCNMA Dicinnamalacetone

DTA Di-p-tolylacetone

DEA Di-p-ethylbenzalacetone

DIPA Di-p-isopropylbenzalacetone

DCLA Di-p-chlorobenzalacetone

DBRA Di-p-bromobenzalacetone

DMeO Di-p-methoxybenzalacetone

DNNMA Di-p-N,N-dimethylaminobenzalacetone

RPMI Roswell Park Memorial Institute medium

FBS Fetal bovine serum

MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

PBS Phosphate-buffered saline

DMSO Dimethylsulphoxide

FT-IR Fourier Transform Infrared

NMR Nuclear Magnetic Resonance

MS Mass spectrometry

ICP-OES Inductively Coupled Plasma Optical Emission Spectrometry

UV-Vis Ultraviolet-Visible

RT-112 Minimally-invasive human bladder carcinoma cell line

EJ-28 Invasive human bladder carcinoma cell line

IC50 Inhibition concentration at 50%

ELISA Enzyme-linked immunosorbent assay

XRD X-ray diffraction

SC-XRD Single Crystal X-ray Diffraction

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CHAPTER 1

1 INTRODUCTION

1.1 General

Medicinal bioinorganic chemistry field blossoming inspired many worldwide

researchers to design and innovate metal-based drugs to be used as anticancer drugs.

Therefore, using transition metals has outweigh the organic-based drugs because of

transition metals have wide range of oxidation and coordination numbers, redox states,

tuneable kinetics and thermodynamics, and structural and geometries diversity of the

substituted ligands (van Rijt& Sadler, 2009). The discovery of cisplatin as anticancer,

about 45 years ago, has making a breakthrough in medicinal inorganic chemistry field

as well as in our understandings to the disease and treatment approaches. The organic

ligands which effectively bonded with metal ions enhanced the overall efficiency and

also driving the innovation in therapy and disease diagnosis areas. Besides, increasing

of therapeutic compounds potency and limiting their side-effects is a common goal in

the field of medicinal chemistry (Jones et al., 2014). To achieve this goal, compounds

are developed to target the disease site or activated by the disease of specific biological

process. The metal complexes which containing the targeting functions or bioactive

ligands or agents activated by specific enzymes provide a new avenues in drug

development (Chiang et al., 2012). Nowadays, after more than 30 years from the

improvement of using cisplatin as a powerful chemotherapeutic agent, still it is the

best-selling anticancer drug in the world. It is used as chemotherapeutic agent to treat

many types of cancer such as bladder, ovarian, head and neck, lymphomas and cervical

cancers. Over many past decades, cispaltin and its derivatives have been ensured as

powerful anticancer agents, while, only two of them (oxaliplatin and carboplatin) have

been used clinically worldwide. Unfortunately, there are some obstacles side-effects

against current platinum drugs such as (van Rijt & Sadler, 2009):-

- Limited efficiency because they are efficient for limited cancer types.

- Some types of tumors may have acquired or intrinsic resistance.

- They have many side-effects like, kidney toxicity, bone narrow suppression

and nausea.

Therefore, there is a big need to discover new compounds to treat many types of cancer

with less side-effects better than cisplatin and its derivatives. New anticancer metal

based compounds development is important challenge for many inorganic chemists to

face the fact that after more than four decades of researches in anticancer field there

are few compounds clinically used as anticancer drug. Based on metal-based

anticancer action mode, metal anticancer compounds can be categorized into five

categories (Gianferrara et al., 2009):-

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(1) The metal in any compound may has the functional role and bind with the

biological target.

(2) The central metal may has structural role and bind through non-covalent

bond with the biological target.

(3) The metal may acts as a good carrier for the active ligands which delivered

in vivo.

(4) The metal compound may acts like catalyst.

(5) The metal compound may behaves as a photo-sensitizer or photoactive.

It is known that the fourth most common cancer among men is bladder cancer. Recent

diagnostic data on this disease showed that men diagnostic four times more than

women. Older people are most affected by bladder cancer than young people. 90% of

people suffer from bladder cancer are older than 55 years old. The average age of

people who diagnosed with bladder cancer is 73 years old (Fosså et al. 2008; Jacobs

et al. 2010; Tiwari & Roy,2012). Recent therapy of bladder cancer are Cisplatin,

Methotrexate, Gemcitabine, Mitomycin, Vinblastine, Doxorubicin, Carboplatin,

Docetaxel, Paclitaxel, 5-Flurouracil (5-FU) and its derivatives (Edson Pontes, 1994;

Galsky& Bajorin,2007; Kaufman et al.,2009; Oosterlinck et al., 2002). They are

general therapy and have many disadvantages such as expensive, difficult to

synthesised, only 25% response to the treatment and many side effects of

chemotherapy like nausea and vomiting, loss of appetite, hair loss, mouth sores,

diarrhea or constipation, increased risk of infections (because of shortage of white

blood cells), bleeding or bruising after minor cuts or injuries due to a shortage of blood

platelets and fatigue because of a shortage of red blood cells (Dasari& Bernard

Tchounwou, 2014; Georg et al.,2012; Koya et al., 2006).

Metal-containing drugs have been used to treat many diseases. The most famous one

is cisplatin, used in late 1978, which is the most effective anticancer drug in the world

(Jemal et al., 2009; Swarts et al., 2008). Cisplatin success has been motivate many

researcher in the past few decades to try another transition metals in term of alternative

searching in metal-base chemotherapeutic area (Jakupec et al., 2008). There is an

urgent issue to synthesise new drugs with less side effects and better selectivity,

activity and bioavailability to treat different types of cancer diseases. Furthermore,

discovering new drugs with non platin metal centre might open new way to develop

useful drugs with fewer side effects (Marcon et al., 2002; Ronconi et al., 2006). There

are many articles highlighted and explained in details the effect of metal complexes

potential in designing of novel drugs (Fricker, 2007; Haas & Franz, 2009; Hambley,

2007; Meggers, 2009; Ronconi& Sadler, 2007; Thompson & Orvig, 2006).

Metal centre in transition metal complexes has intrinsic nature, accessible redox state,

distinctive coordination modes, and tuneable kinetic and thermodynamic properties

drive the transition metal complexes to add more potential advantages more than the

organic ligand in the complexes (van Rijt& Sadler, 2009). Furthermore, metal

reactivity in the complexes not only controlled by ligands but also the ligands play

important roles in the biological activity (Gianferrara et al.,2009). In the few last

decades there were a great expansion researches happened in the field of coordination

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chemistry of nitrogen-sulphur containing Schiff bases compounds such as

thiosemicarbazides, dithiocarbazates and their organic derivatives (Akbar Ali et

al.,1974; Beraldo, 2004; Pelosi, 2010).Transition metal complexes derived from

Schiff bases have been played an important role to develop coordination chemistry.

Furthermore, the synthesis and application of Schiff bases and their metal complexes

add more attention on this area. Schiff bases can be synthesized by the condensation

reaction between aliphatic or aromatic aldehydes or ketonesand primary amines. The

yielded imine (R-C=N-R’) can be used as a chelating ligands for the metal complexes

preparation which are useful and can be used in many biological and industrial

applications (Kumar et al.,2009; Soliman et al.,2007). This type of Schiff bases

possess two types of donor atoms soft nitrogen and hard sulphur. They have the ability

to act as a good chelating agent for various transition metals (Mohamed et al.,2009).

The bioactivity and flexibility of sulphur and nitrogen containing ligands associated

with the presence of both thioamino (-(C=S)-NH-) and imino (-HC=N-) in their

structures moieties (Stringer et al., 2011). Many advantages can be gain from

synthesizing these metal complexes such as: chelating of metals with such Schiff bases

enhances their biological activity, easy preparation and low coast (Perrin & Chang,

2016).

1.2 Dibenzalacetone Ketones

Aldol condensation reaction like Grignard reaction both are useful carbon-carbon

bond-forming organic reaction. Aldol condensation reaction can be used to synthesize

unsaturated ketones by reacting aliphatic or aromatic aldehyde with ketone in the

presence of mineral acid or alkaline base. This type of reaction is usually used in

organic reaction to form bigger ketones with C-C bonds (Carey et al., 2008). This type

of reaction contains two steps the first step called Aldol reaction while the second step

called elimination reaction for both acid and base Aldol condensation (Carey et al.,

2000). Base catalyzed Aldol condensation can be proceeds by using sodium hydroxide

or potassium hydroxide.

Dibenzalacetone is a conjugated symmetric chalcone contains two benzene rings

connected by unsaturated aliphatic chain with carbonyl group as shown in Figure1.1.

X X

O

Figure 1.1 : General chemical structure of dibenzalacetone

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Table1.1 represents dibenzalacetone derivatives.

Table 1.1 : Dibenzalacetone derivatives used in this study

X Compound name Abbreviation Reference

H Dibenzalacetone DBA (Conard et al., 1932)

CH3 Di-p-tolylacetone DTA (Arshadet al., 2008)

C2H5 Di-p-ethylbenzalacetone DEA New compound

CH(CH3)2 Di-p-isopropylbenzalacetone DIPA New compound

Cl Di-p-chlorobenzalacetone DCLA (Butcher et al., 2007)

Br Di-p-bromobenzalacetone DBRA New compound

OCH3 Di-p-methoxybenzalacetone DMeO (Handani et al., 2008)

N(CH3)2 Di-p-N,N-dimethylbenzalacetone DNNMA New compound

Unsymmetrical chalcones, type from flavonoids family, are naturally occurring

compounds in many edible plants such as fruits, spices and vegetables which are non-

toxic to normal cells. While, symmetrical chalcones like dibenzalacetone and

dicinnamalacetone are not naturally occurring compounds. Dibenzalacetone can be

synthesized by using Aldol condensation from the reaction between two moles of

benzaldehyde or its derivatives and one mole of acetone (Youg et al., 2016). Figure

1.2 explains the reaction mechanism of base catalyzed Aldol condensation to

synthesized dibenzalacetone ketone in the following main steps (Kim et al., 2016;

Perrin et al., 2016):-

- First step: - Deprotonation of acetone by potassium hydroxide or sodium

hydroxide and produce nucleophilic enolate.

- Second step: - The nucleophile attacks thye electrophile which is benzaldehyde

or its derivatives to give alkoxide.

- Third step: - Protonation of alkoxide to produce neutral hydroxylketone.

- Fourth step: - Deprotonation again of hydroxyl-ketone to make nucleophilic

enolate (hydroxyenolate).

- Fifth step: - Elimination of hydroxide ion to produce benzalacetone

(monoaddition).

- Sixth step: - Repeat steps one to five again to produce the final product

dibenzalacetone or its derivatives.

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Figure 1.2 : Base catalyzed Aldol condensation mechanism (Kim et al., 2016)

Dibenzalacetone derivatives can be synthesized by using benzaldehyde derivatives

instead of un-substituted benzaldehyde.Dibenzalacetone or dibenzylideneacteone is

used as an ingredient in sunscreen cream and also as a ligand in organometallic

chemistry in the synthesis of palladium(0) complexes (Ogasawara et al., 2001). Para

substituted dibenzalacetone can be synthesized by the following Aldol condensation

procedure with para substituted benzaldehyde. In the same manner, dicinnamalacetone

(Figure 1.3) can be synthesized by using also base catalyzed Aldol condensation with

using cinnamaldehyde instead of benzaldehyde.

O

Figure 1.3 : Chemical structure of dicinnamalacetone DCNMA

(da Silva et al., 2018)

These ketones have many features:-

- These compounds are symmetrical chalcones.

- These compounds have long double-single bond conjugation system.

- Many types of functional groups can be substituted on the benzene ring.

- By varying the number of substituted group and the type of substituted group

on the two benzene rings it is easy to direct the electron density.

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1.3 Dithiocarbazate

Dithiocarbazate compounds are sulphur-nitrogen containing compounds which have

the structural analogy to semicarbazides, thiosemicarbazides and carbazates as shown

in Figure 1.4.

NH

H2NNH2

O

(a)

NH

H2NO

O

(b)

R

NH

H2NNH2

S

(c)

NH

H2NS

S

(d)

R

Figure 1.4 : Molecular structure of (a) semicarbazide, (b) carbazate, (c)

thiosemicarbazide and (d) dithiocarbazate

The origin of this type of organic compounds is not well-known but the earliest

publication on these compounds was made on 1905 (Dunlap, 1905) who synthesized

Schiff base derived from phthalic anhydride and phenylsemicarbazide. In 1946

Domagk studied the antitubercular activity of some thiosemicarbazide derivatives

(Domagk et al., 1946). Another important finding in 1970 it was reported on the

cytotoxicity of thiosemicarbazide derivatives which were synthesized from

thiosemicarbazide and aminopyridine-2-carboxaldehyde (Meldrum et al., 1970). The

first publication on dithiocarbazate derivatives was reported in the chemistry of their

metal complexes (Ali et al., 1972).

Dithiocarbazate is an organic amine containing two nitrogen atoms and two sulphur

atoms as shown in Figure1.5. Ali and Livingstone was first toreview on the chemistry

of this type of organic compound which was used to synthesize different compounds

of Schiff bases (Akbar et al., 1974). Since then, many derivatives of dithiocarbazate

compounds had been synthesized and applied in different applications.

The researchers in this field mostly focused on S-benzyl and S-methyldithiocarbazate

(Ali et al., 1978; Rao et al., 1965; Tofazzal et al., 2000) while the others studied

recently (Antony et al., 2014; Begum et al., 2015a; Begum et al., 2015b; Low et al.,

2016; Mirza et al., 2014).

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1.4 Schiff bases

Schiff base has the general chemical structure as shown in the Figure1.5. It is manly

produce from reacting primary amine with ketone or aldehyde.

C N R

Figure 1.5 : Chemical structure of Schiff base

Many nitrogen-sulphur Schiff bases have been synthesized from the condensation of

dithiocarbazate derivatives with aliphatic and aromatic aldehydes and ketones.

Dithiocarbazate Schiff bases have tautomeric resonance which is called thione-thiol

reseonance as shown in Figure1.6 (Krasowska et al., 2010).

RS

S

NH N

R'

Thione Form

RS

N N

R'

SH

Thiol Form

Figure 1.6 : Thione-Thiol tautomerism

Thiosemicarbazide Schiff bases coordinate with transition metal ions in both thione

and thiol forms (De Lima et al., 1999). In the same manner, dithiosemicarbazide Schiff

bases appear in the thione form when coordinate with transition metal complexes

(Hossain et al., 1996).

In this study, nine Schiff bases have been synthesised from reacting SBDTC with

dibenzalacetone, dibenzalacetone derivatives and dicinnamalacetone. The reaction

between SBDTC and the synthesised ketones was catalyzed by hydrochloric acid or

acetic acid. The reaction scheme illustrated in Figure1.7.

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S NH

S

NH2+

O

R R

NNH

SS

R R

S NH

S

NH2+

O

NNH

SS

DCNMASB

Ketone DBA Schiff Base DBASBSBDTC

SBDTC DCNMA

R Ketone Schiff Base

- H Dibenzalacetone (DBA) DBASB

- CH3 Di-p-tolylacetone (DTA) DTASB

- C2H5 Di-p-ethylbenzalacetone (DEA) DEASB

- CH(CH3)2 Di-p-isopropylbenzalacetone (DIPA) DEASB

- Cl Di-p-chlorobenzalacetone (DCLA) DCLASB

- Br Di-p-bromobenzalacetone (DBRA) DBRASB

- OCH3 Di-p-methoxybenzalacetone (DMeO) DMeOSB

- N(CH3)2 Di-p-N,N-dimethylaminobenzalacetone (DNNMA) DNNMASB

Figure 1.7 : Reaction scheme of Schiff bases synthesis and chemical structure of

the synthesized Schiff bases

1.5 Metal complexes

It is well known that the drug action can be accelerated by metal complexes and

therapeutic efficiency can be enhanced by the coordination with transition metal ions

(Navarro et al., 2004; Raman et al., 2008; Sánchez-Delgado et al., 1996). Biological

activity of metal complexes highly depends on the transition metal and the donor

ligand. The observation from different published articles on metal complexes of NS

donor Schiff bases showed that nickel, copper and zinc complexes have good activity

against Human T-lymphoblastic leukemia cell (CEM-SS) with low CD50 values 2.0-

3.4 g cm-3. While cadmium complexes showed moderate activity against cervical

cancer cells (HELA) and CEM-SS cell with CD50 values 4.0 and 4.95 g cm-3,

respectively (Tarafder et al., 2002a).

To summarize briefly, this thesis aimed to study the effect of aromatic dithiocarbazate

(SBDTC), double bond-single bond conjugation system (highly conjugated ketones),

vital transition metals and the effect of functional group substituted on para position

of both benzene rings on the cytoxicity of these metal complexes against two types of

bladder cancer cell lines which are invasive human bladder carcinoma cell line (EJ-

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28) and minimally invasive human bladder carcinoma cell line (RT-112). The target

metal complexes were synthesized and characterized. The five divalent transition

metals were chosen in this study due to their biological lability and inertness (Figure

1.8). While, Cd(II) and Zn(II) were the most labile (Blusch et al., 2013; Karlin, 2012).

Their vital presence in biological systems and many enzymes, as outlined previously,

were also chosen as important aspects in their selection in this study.

Figure 1.8 : General chemical structure of the transition metal complexes

Table 1.2 shows the metal complexes which have been synthesised in this study.

Table 1.2 : The synthesised transition metal complexes

X M Name X M Name

Hydrogen H

Ni(II) NiDBASB

Methyl

CH3

Ni(II) NiDTASB

Cu(II) CuDBASB Cu(II) CuDTASB

Fe(II) FeDBASB Fe(II) FeDTASB

Cd(II) CdDBASB Cd(II) CdDTASB

Zn(II) ZnDBASB Zn(II) ZnDTASB

Ethyl

C2H5

Ni(II) NiDEASB

isopropyl

CH(CH3)2

Ni(II) NiDIPASB

Cu(II) CuDEASB Cu(II) CuDIPASB

Fe(II) FeDEASB Fe(II) FeDIPASB

Cd(II) CdDEASB Cd(II) CdDIPASB

Zn(II) ZnDEASB Zn(II) ZnDIPASB

Chloro

Cl

Ni(II) NiDCLASB

Bromo

Br

Ni(II) NiDBRASB

Cu(II) CuDCLASB Cu(II) CuDBRASB

Fe(II) FeDCLASB Fe(II) FeDBRASB

Cd(II) CdDCLASB Cd(II) CdDBRASB

Zn(II) ZnDCLASB Zn(II) ZnDBRASB

Methoxy

OCH3

Ni(II) NiDMeOSB

N,N-

dimethylamino

N(CH3)2

Ni(II) NiDNNMASB

Cu(II) CuDMeOSB Cu(II) CuDNNMASB

Fe(II) FeDMeOSB Fe(II) FeDNNMASB

Cd(II) CdDMeOSB Cd(II) CdDNNMASB

Zn(II) ZnDMeOSB Zn(II) ZnDNNMASB

N

X X

N

S S N

XX

N

SS

M

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1.6 Cytotoxicity

The biological activity of a chemical species can be explained by experimental and

computational methods. There are a lot of theoretical studies about the determination

of chemical activity. Generally, quantum chemical descriptors are used to determine

the ranking of biological activities (Sayin & Karakas, 2013). The examples of these

parameters include the highest occupied molecular orbital energies (HOMO), the

lowest unoccupied molecular orbital energies (LUMO), the energy gap between

LUMO and HOMO, hardness or softness of the molecules or atoms and the global

electronegativity. The biological activities closely depend on the separation of the

LUMO and HOMO in a molecule. The bending ability of an inhibitor to the

appropriate molecule will increase with the increase of the HOMO and decrease of the

LUMO of complex ions. This due to the ability of electrons to transfer to the acceptor

molecule and the strong electron accepting ability of the molecules. The smaller the

energy gap between HOMO and LUMO, the more active the molecule is in the term

of biological properties. This because the electrons are easily excited from the lower

energy orbital to higher energy orbital (Zhang et al., 2012). Besides that, soft

complexes (complexes in which sulphur atoms act as donor atoms) have a small

energy gap between the molecular orbital and can interact easily with biological

molecules. Hence, the biological activity is increased with the increase of softness of

the complexes. Cytotoxicity of some sulphur-nitrogen ligands and their metal

complexes is based on four main criteria. Firstly, the complex should be reasonably

labile. Zinc and cadmium complexes are the most labile with d10 configurations.

Secondly, the metal chelate should have reasonably high thermodynamic stability. The

metals used on complexation should be (b) class metals (4d metals), in particular

palladium and platinum due to its similarity to cisplatin, a common anticancer drug

used in cancer treatment. Complexes or ligands with sulphur acting as donor atoms

are the most likely to be effective drugs. This is because they allow for lipid solubility

of the stable metal complexes (Ali et al., 2011).

Besides, some studies on the behaviour of bladder cancer cells shown that acidic

environments help bladder cancer cells grow. From this point, synthesizing of alkaline

or neutral metal complexes may raises pH level and make the body more alkaline and

cure or prevent bladder cancer. While, some in vitro studies on cancer cells do not

represent the complex acidity or basicity nature of how tumors behave in vivo or in

the human body (Ali & Livingstone, 1974).

1.7 Problem statements

Globally, bladder cancer is the fourth most common type of cancer in men. General

therapy such as Cisplatin, Methotrexate, Gemcitabine, Mitomycin, Vinblastine,

Doxorubicin, Carboplatin, Docetaxel, Paclitaxel, 5-Flurouracil (5-FU) and its

derivatives are still used in the treatment of bladder cancer and also they are used to

treat many types of cancer. The side effects of these chemotherapies include nausea,

vomiting, loss of appetite, hair loss, mouth sores, diarrhea or constipation, increased

risk of infections (because of a shortage of white blood cells), bleeding or bruising

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after minor cuts or injuries (due to a shortage of blood platelets), fatigue (because of

a shortage of red blood cells) are very severe. Thus there is a need to identify,

efficacious anti-cancer drugs that are less toxic. Besides, the electron density can be

directed to the complex centre which is transition metal by using symmetrical

chalcones better than using unsymmetrical chalcones. Therefore, the cytotoxicity of

the synthesized metal complexes solution dissolved in DMSO as a solvent was

determined which are non-toxic due to the nontoxicity of dibenzalacetone which are

chalcones. The advantage of using these aromatic chalcones is to synthesise chalcones

substituted with many functional groups after studying the effect of functional group

against bladder cancer cells. The cytotoxicity of dithiocarbazate metal complexes have

been studied by many researchers against many types of cancer. Unfortunately, there

is a very little research on using dithiocarbazate complexes as an anticancer agents

against bladder cancer. The previous works on testing dithiocarbazate complexes

against different types of cancer cells showed significant activity. The previous studies

showed that the metal complexes of Cu2+, Ni2+, Cd2+, and Zn2+ were active compounds

against cancer cells. In the same manner, these metal complexes derived from SBDTC

and symmetrical dibenzalacetone are expected to show significant activity against

bladder cancer cells due to their lipholicity and ability to penetrate lipid permeable

membrane of cancer cell. Then, ligands (Schiff base) used to transport and address the

compounds to the specific site of cancer cell. This research will not study the toxicity

of the synthesised compounds against normal bladder cells because of the slow growth

of normal bladder cells and the concentration of the tested compounds is less than the

toxic concentration of dithiocarbazate metal complexes which is more than 10 M.

1.8 Objectives

This study was conducted to synthesizeand fully characterize dithiocarbazate derived

from S-benzyldithiocarbazate and highly conjugated ketones and their metal

complexes. Besides, this study aimed to test the cytotoxicity activity against two types

of bladder cancer cell lines EJ28 & RT112. The toxicity of the synthesised complexes

will not tested in this study because normal bladder cells grow at much slower rate in

induced conditions compared to cancer cells. Besides, bladder cancer cells mutate and

not typically like normal cells and making the test inaccurate. Secondly, normal

bladder cells tend to get contaminated and died very easly compared to cancer cells

which means sustaining enough cells for analysis is difficult. The main objectives of

this study include:

To synthesise and characterize nine symmetrical ketones with highly conjugated

system via base catalysed Aldol condensation.

To synthesise and characterize nine novel Schiff bases derived from the above

symmetrical ketones and S-benzyldithiocarbazate by acid catalised condensation.

To synthesise and characterize 45 novel metal complexes derived from the above

Schiff bases and five divalent transition metals which are Ni(II), Cu(II), Fe(II),

Zn(II) and Cd(II).

To elucidate the cytotoxic activity of the Schiff bases and their metal complexes

against two types from bladder cancer cell lines (EJ28 & RT112).

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