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A novel series of titanocene dichloride derivatives: synthesis, characterization and assessment of their cytotoxic properties by Gregory David Potter A thesis submitted to the Department of Chemistry in conformity with the requirements for the degree of Doctor of Philosophy Queen’s University Kingston, Ontario, Canada May, 2008 Copyright © Gregory David Potter, 2008 Abstract Although cis-PtCl2(NH3)2 (cisplatin) has been widely used as a chemotherapeutic agent, its use can be accompanied by toxic side effects and the development of drug resistance. Consequently, much research has been focused on the discovery of novel transition metal compounds which elicit elevated cytotoxicities coupled with reduced toxic side effects and non-cross resistance. Recently, research in this lab has focused on preparing derivatives of titanocene dichloride (TDC), a highly active chemotherapeutic agent, with pendant alkylammonium groups on one or both rings. Earlier results have demonstrated that derivatives containing either cyclic or chiral alkylammonium groups had increased cytotoxic activities. This research therefore investigated a new series of TDC complexes focusing specifically on derivatives bearing cyclic and chiral alkylammonium groups. A library of ten cyclic derivatives and six chiral derivatives were synthesized and fully characterized. These derivatives have undergone in vitro testing as anti-tumour agents using human lung, ovarian, and cervical carcinoma cell lines (A549, H209, H69, H69/CP, A2780, A2780/CP and HeLa). These standard cell lines represent solid tumour types for which new drugs are urgently needed. The potencies of all of the Ti (IV) derivatives varied greatly (range from 10.8 μM - >1000 μM), although some trends were observed. In general, the dicationic analogues exhibited greater potency than the corresponding monocationic derivatives. Additionally, the cyclic analogues bearing 1,3- and 1,4- ii substituted pyridines displayed potent cytotoxic activities (IC50> 20 μM). It was also found at concentrations of ~30 μM that the derivatives bearing an ephedrine derived substituent were cytotoxic. Conversely, analogues substituted with piperidinyl, morpholinyl or primary alkylammonium groups were inactive (>200 μM) against the cancer cell lines assayed. iii Acknowledgements There have been a lot of people that have played a significant role in my life over the past few years while I was at Queen’s. First and foremost, I would like to thank my supervisor and mentor Mike Baird. He has always been caring, patient and a diligent driving force for me to improve myself. I always appreciated his dedication to his students and their professional development. His passion for chemistry has always been inspiring. I would also like to acknowledge all of the past and present members of the Baird lab. Most notably I wish to thank John Brownie, Goran Stojcevic and Emily Mitchell all of whom have made this experience more enjoyable. I also wish to thank my co- supervisors Dr. Susan P.C Cole and Dr. Philip G. Jessop. As well, I wish to thank Marina Chan and Kathy Sparks for their work with the MTT assays. Thank you to all of my friends that I have made at Queen’s over the past few years. I am grateful for all of the support and words of encouragement from my friends and family outside of the lab. I would also like to acknowledge all of the past students that I have taught throughout my tenure in graduate school. I have always enjoyed teaching and my relationship with the students has made this experience far more rewarding. Most importantly, I wish to thank my caring and supportive girlfriend Jennifer. I don’t know how you put up with me over these past years, but I am sure glad that you did. Thank you for always being there when I needed you the most. iv Statement of Co-Authorship and Originality Unless specifically stated otherwise, the author under the supervision of Professor Michael C. Baird and Professor S.P.C Cole performed all of the research presented in this thesis. This research reports the synthesis, characterization and cytotoxic activity of a series of sixteen TDC derivatives bearing cyclic and chiral alkylammonium groups against various cancer cell lines. v Table of Contents Abstract................................................................................ ii Acknowledgements ........................................................... iv Statement of Co-Authorship and Originality.................... v Chapter 1: Introduction ..................................................... 1 1.1 Cancer and the need for new treatments ............................................... 1 1.2 Discovery and development of cisplatin as a chemotherapeutic agent .. 2 1.3 Mechanism of action of cisplatin............................................................. 3 1.4 The pursuit of more effective analogues of cisplatin............................... 6 1.5 Development of metallocenes as chemotherapeutic agents .................. 7 1.6 Aqueous chemistry of titanocene dichloride ........................................... 9 1.7 The uptake and delivery of titanocene dichloride in vivo ...................... 13 1.8 Interactions of titanocene dichloride with DNA ..................................... 17 1.9 Radiolabeling using Titanium-45 .......................................................... 19 1.10 Titanocene dichloride analogues with varied anionic ligands ............... 21 1.11 Modification of the cyclopentadienyl ligands ........................................ 24 1.12 Preparation of TDC derivatives containing alkylammonium groups ..... 33 1.13 Different methodology in preparing titanocene dichloride derivatives... 35 1.14 Research Objectives ............................................................................ 37 Chapter 2: Experimental.................................................. 41 vi 2.1 General ................................................................................................ 41 2.2 X-Ray Crystal Structure Determination ................................................ 42 2.3 Preparation and Characterization of Compounds ................................ 43 2.4 MTT bioassay protocol ......................................................................... 82 Chapter 3: Results and Discussion................................ 85 3.1 Synthesis of (1R, 2S)-N-Methylephedrine ............................................ 85 3.2 Chlorination of (1R, 2S)-N-Methylephedrine and Alaninol.................... 86 3.2 Syntheses of Cyclic Aminoalkylcyclopentadienes (14a – 20a)............. 89 3.3 Results from the syntheses of Lithium Cyclic Aminoalkylcyclopentadienide salts (14b – 20b).............................................. 94 3.4 Results from the syntheses of monocationic titanocene dichloride analogues (14c – 20c) .................................................................................... 99 3.5 Results for the syntheses of the dicationic titanocene dichloride analogues (14d – 20d).................................................................................. 105 3.6 Characterization by NMR Spectroscopy of the monocationic titanocene dichloride complexes 14c – 20c.................................................................... 112 3.7 NMR spectroscopic characterization of the dicationic titanocene dichloride complexes 14d – 20d. .................................................................. 120 3.8 Characterization of mono- and dicationic complexes (14c,d – 20c,d) by elemental analysis. ....................................................................................... 129 3.9 Characterization of Mono- and Dicationic derivatives (14c,d – 20c,d) by Mass Spectrometric Analysis. ....................................................................... 130 vii 3.10 Characterization of mono- and dicationic titanocene dichloride derivatives by X-ray crystallography. ............................................................ 134 3.11 Summary of the Results for the Syntheses and Characterization of the Mono- and Dicationic titanocene dichloride derivatives. ............................... 140 3.12 Determination of Cytotoxicity for the Titanocene Dichloride Derivatives by MTT in vitro assays. ................................................................................. 141 3.13 Effect of substitution on Cytotoxicity of Titanocene Dichloride Derivatives 14c,d – 20c,d............................................................................. 149 Chapter 4: Summary and Conclusions........................ 152 References....................................................................... 154 viii List of Figures Figure 1 cis-Diamminedichloroplatinum(II). ................................................... 2 Figure 2 A representation of a DNA strand highlighting the four bases, and 17 the preferred binding sites of cisplatin. ......................................... 4 Figure 3 Structures of platinum containing compounds (carboplatin 1, 28 oxaliplatin 2). The cis leaving groups are highlighted in red. ....... 6 5 Figure 4 Bis (η -Cp) titanium(IV) dichloride, or titanocene dichloride (TDC). 8 50,51 Figure 5 Chloride hydrolysis equilibria for TDC. ...................................... 9 Figure 6 Hydrolysis of the Cp ligand generates cyclopentadiene and a titanium hydroxide species............................................................ 10 Figure 7 The complex equilibria resulting from the dissolution of TDC in 53 water at physiological pH ~ 7.4. .................................................
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