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Polypyridyl Complexes with Oo'-, Ono'-, Or No-Chelating Coligands

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Polypyridyl Complexes with Oo'-, Ono'-, Or No-Chelating Coligands SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL PROPERTIES OF METAL(II) POLYPYRIDYL COMPLEXES WITH OO'-, ONO'-, OR NO-CHELATING COLIGANDS CHIN LEE FANG MASTER OF SCIENCE FACULTY OF SCIENCE UNIVERSITI TUNKU ABDUL RAHMAN JUNE 2013 SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL PROPERTIES OF METAL(II) POLYPYRIDYL COMPLEXES WITH OO'-, ONO'-, OR NO-CHELATING COLIGANDS By CHIN LEE FANG A thesis submitted to the Department of Chemical Science, Faculty of Science, Universiti Tunku Abdul Rahman, in partial fulfillment of the requirements for the degree of Master of Science JUNE 2013 ABSTRACT SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL PROPERTIES OF METAL(II) POLYPYRIDYL COMPLEXES WITH OO'-, ONO'-, OR NO-CHELATING COLIGANDS Chin Lee Fang Exploring the combination of ligands and metal(II) ion to form ternary metal complexes is an attempt to gain insight into rational design of metal complexes for specific application, such as anticancer drug. 1,10- phenanthroline (phen) has been chosen as the main ligand and as an intercalator. This kind of ternary metal(II) complexes allows intercalation of phen ligand between the DNA nucleobase pairs and orientation of the coligand(s) to interact with nucleobases in their vicinity. Maltol, dipicolinic acid and threonine have been chosen as coligands partly because their non- toxicity may results in lower toxicity of metal(II) complexes. The coordinated maltolate has H-acceptor site, dipicolinate have two H-acceptor sites whereas threonine has both H-acceptor and H-donor sites. This study compares the effect of three coligands, the number of chelated coligand and the types of metal(II) ion on the physical and biological properties of resultant ternary metal(II) complexes. The complexes were characterized by elemental analysis, FTIR, UV-Vis and FL spectroscopy, X-ray diffraction, molar conductivity, ESI-MS, TGA and CD spectroscopy. Based on the elemental analysis, molecular formulae of the synthesised metal(II) complexes are [Co(C12H8N2)(C6H5O3)Cl]·4H2O (1), [Cu(C12H8N2)(C6H5O3)Cl]·½H2O (2), [Zn(C12H8N2)(C6H5O3)Cl]·1½H2O (3), [Co(C12H8N2)(C6H5O3)(C6H5O3)]·5H2O (4), [Co(C12H8N2)(C7H3NO4)(H2O)]·2H2O (5), {[Cu2(C12H8N2)3(C7H4NO4)(H2O)][Cu(C7H3NO4)2]·[(11H2O)(CH3OH)]} (6), [Zn(C12H8N2)(C7H3NO4)(H2O)]·H2O (7), [Cu(C4H8NO3)(C12H8N2)(H2O)Cl]·2H2O (8 - 9) and [Zn(C4H8NO3)(C12H8N2)(H2O)Cl]·2H2O (10 - 11) [phen = C12H8N2; maltolate = C6H5O3; μ-dipicolinate = C7H4NO4; dipicolinate = C7H3NO4; threoninate = C4H8NO3]. X-ray structure analyses show that complexes 4 - 5 and 7 - 11 have octahedral geometry about the central metal(II) ion. Complex 6 is a trinuclear complex with a bridging dipicolinate ligand. A change in the type of metal(II) ion, coligand and the number of coordinated ligands influence the FL emission intensities but not the λmax and the shape of the bands. Most of the studied compounds are 1:1 electrolyte except for complexes 4, 5 and 7 which are non- electrolytes in water-methanol (1:1 v/v) solution. Based on the molar conductance and ESI-MS obtained, metal(II) complexes studied were found to be stable within the duration of the measurement up to 24 hours except for the neutral [Co(phen)(maltolate)2]. The lability of the metal complexes studied appears to depend on the type of metal, nature of the coordinated ligand and the number of the coordinated ligand. The complexes 8 - 11 are optically active and they are grouped into two pairs of enantiomers based on their CD spectra. However, there are no significant differences observed for each enantiomer pair of complexes in FTIR, CHN, UV-Vis, FL, molar conductivity, ESI-MS and TGA. Meanwhile, two groups of metal(II) complexes viz. Co(II) complexes (1 and 4) and Zn(II) complexes (7 and 10) were selected to investigate the effect of changing the coligand on their biological properties. It is believed that the type of coordinated ligand is a crucial factor in bestowing the binding site specificity and selectivity of a given metal complex. Moreover, not many Co(II) and Zn(II) complexes have been studied for their anticancer properties. Hence, it will be interesting to find out the biological properties of Co(II) complexes (1 and 4) and Zn(II) complexes (7 and 10). Indeed, a change of coligand and the number of chelated ligands of Co(II) and Zn(II) complexes seem to influence their DNA recognition, topoisomerase I inhibition and antiproliferative properties. Both Zn(II) complexes (7 and 10) can inhibit topoisomerase I, and have better anticancer activity than cisplatin against nasopharyngeal cancer cell lines, HK1 and HONE-1, with IC50 values in low µM range. [Zn(phen)(L-threoninate)(H2O)Cl]·2H2O (10) has the highest therapeutic index for HK1 (3.9). Both Zn(II) complexes (7 and 10) can induce cell death by apoptosis. Changing the coligand in the Zn(II) complexes (7 and 10) affects the biological properties of the complexes such as the binding affinity for some DNA sequences, nucleobase sequence-selective binding, the phase at which cell cycle progression was arrested for treated cancer cells and their therapeutic index. ACKNOWLEDGEMENTS Foremost, I offer my sincerest gratitude to my main supervisor, Dr. Ng Chew Hee and co-supervisor, Dr. Neo Kian Eang for the continuous support of my master study and research, for their patience, motivation, enthusiasm, and immense knowledge. This thesis would not have been completed or written without the guidance and the help of several individuals who in one way or another contributed and extended their valuable assistance in the preparation and completion of this study. I wish to acknowledge the efforts of the staff from Chemical, Molecular and Materials Analysis Centre (CMMAC), National University of Singapore (NUS), for helping me carrying out the Electrospray Ionisation Mass Spectrometry (ESI-MS). My sincere thanks also goes to Prof. Leong Weng Kee from Nanyang Technological University (NTU), Dr. Koh Lip Lin, Ms. Tan Geok Kheng and Ms. Hong Yimian from NUS and Prof. Ng Seik Weng from University Malaya for helping with the X-ray crystallographic studies. The Director General of Health Malaysia is acknowledged for part of the anticancer work done in the Institute for Medical Research. Siew Ming, Hoi Ling, Yee Lian and James Chong are acknowledged for being great help in conducting part of the biological studies. Special thanks go to colleagues in the Department of Chemistry: Wai San, Kok Leei, Teck Leong, Nicholas, Jason and to those who have helped me during my stay in Universiti Tunku Abdul Rahman (UTAR). I would like to thank UTARRF for an internal grant (UTARF6200/N03) and the Malaysian Government and MOSTI for the eScience grant 02-02-11-SF0033. I would also like to thank Ministry of Higher Education Malaysia (MOHE) for their scholarship to allow me to pursue master degree in UTAR. Last but not the least, my family members for supporting me spiritually throughout my life and Mr. Chu Chee Kiat, who was always there to cheer me up and stood by me through the good times and bad. APPROVAL SHEET This dissertation/thesis entitled “SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL PROPERTIES OF METAL(II) POLYPYRIDYL COMPLEXES WITH OO'-, ONO'-, OR NO-CHELATING COLIGANDS” was prepared by CHIN LEE FANG and submitted as partial fulfillment of the requirements for the degree of Master of Science at Universiti Tunku Abdul Rahman. Approved by: ___________________________ (Assoc. Prof. Dr. Ng Chew Hee) Date:………………….. Supervisor Department of Chemical Science Faculty of Science Universiti Tunku Abdul Rahman ___________________________ (Asst. Prof. Dr. Neo Kian Eang) Date:………………….. Co-supervisor Department of Chemical Science Faculty of Science Universiti Tunku Abdul Rahman FACULTY OF SCIENCE UNIVERSITI TUNKU ABDUL RAHMAN Date: __________________ SUBMISSION OF THESIS It is hereby certified that CHIN LEE FANG (ID No: 09ADM09166) has completed this thesis entitled "SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL PROPERTIES OF METAL(II) POLYPYRIDYL COMPLEXES WITH OO'-, ONO'-, OR NO-CHELATING COLIGANDS” under the supervision of Associates Prof. Dr. Ng Chew Hee (Supervisor) from the Department of Chemical Science, Faculty of Science, and Assistance Prof. Dr. Neo Kian Eang (Co-Supervisor) from the Department of Chemical Science, Faculty of Science. I understand that University will upload softcopy of my thesis in pdf format into UTAR Institutional Repository, which may be made accessible to UTAR community and public. Yours truly, ____________________ (CHIN LEE FANG) DECLARATION I hereby declare that the dissertation is based on my original work except for quotations and citations which have been duly acknowledged. I also declare that it has not been previously or concurrently submitted for any other degree at UTAR or other institutions. Name : ______________________ Date : _______________________ TABLE OF CONTENTS Page ABSTRACT ii ACKNOWLEDGEMENTS v APPROVAL SHEET vii SUBMISSION SHEET viii DECLARATION ix LIST OF TABLES xiii LIST OF FIGURES xv LIST OF ABBREVIATIONS xviii CHAPTER 1.0 INTRODUCTION 1.1 General 2 1.2 Objectives 10 2.0 LITERATURE REVIEW 2.1 1,10-phenanthroline complexes 15 2.2 Maltolato complexes 19 2.3 Dipicolinato complexes 25 2.4 Threoninato complexes 32 2.5 Comparative review of biological studies of cobalt(II), 39 copper(II) and zinc(II) complexes 2.6 Summary 44 3.0 SYNTHESIS AND CHARACTERIZATION OF METAL(II) 1,10-PHENANTHROLINE COMPLEXES WITH O,O'- MALTOL, [M(phen)(ma)Cl]·xH2O (M(II) = Co, Cu, Zn) and [Co(phen)(ma)2]·5H2O 3.1 Introduction 48 3.2 Experimental 3.2.1 Materials and reagents 49 3.2.2 Preparation of [M(phen)(ma)Cl]·xH2O (M =
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