And 1,7-Carborane Ligands for Boron Neutron Capture Therapy
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YO t' Lg-3^o Ptatinum(Il) Complexes Containing lr2' and lr7-Carborane Ligands for Boron Neutron Capture Therapy A Thesis Submitted Towards the Degree of Doctor ofPhilosophy by Jean Ann Todd B.Sc. (Hons) * * a ADELAIDE * t UNIVERSITY t- AUSTRALIA cRucr L Department of Chemistry October 2001 Contents Acknowledgements IX Statement x Abstract xl Abbreviations xiii Chapter I : Introduction I l.l Cancer 1.1.1 Current Cancer Therapy 2 1.1.2 Binary Systems 2 l.l.2.l The Neutron Capture Reaction 2 1.2 Boron Neutron Capture Therapy J 1.2.1 The Advantages of BNCT J 1.2.2 Optimisation of BNCT 4 1.2.3 Application of BNCT 5 1.2.3.1 The Blood-Brain Barrier 5 1.2.4 Early Trials of BNCT 6 1.2.5 Recent Advances in BNCT 8 1.2.5.1The Carboranes 8 l.2.5.2Types of BNCT Agents 9 1.3 Tumour Selective Agents l0 1.3.1 Cellular Builcling Blocks l0 I 1.3.1. I Boron-Containing Nucleic Acid Precursors I .3.1.2Boron-Containing Amino Acids 1.3.1.3 Lipids, Phospholipids and Carbohydrates 1.3.2 Lipoproteins 1.3.3 Liposomes 1.3.4 Receptor / Antigen Binders 1.3.4.1Antibodies l-3.4.2Growth Factors 1.3.4.3 Hormones 1.3.5 Porphyrins 1.4 DNA Targeting Agents for BNCT 1.4.1 AlkylatingAgents L4.2 DNA Intercalators 1.4.3 Groove Binders I.4.4 Polyamines 1.4.5 Nucleic Acid Precursors 1.5 Background of platinum anti-cancer drugs 1.5.1 Cisplatin 1.5.1 .1 Activity and Action of Cisplatin 1.5.1.2 Problems Associated with the Use of Cisplatin in Cancer Therapy 1.5.2 New Generations of Platinum Anti-tumour Complexes 1.5.2.1Carboplatin 1.5.2.2 Other analogues of Cisplatin and Carboplatin- Structure-Activity Relationships ll 1.5.2.3 Discovery of C¡otoxic Complexes Violating the Structure-Activity Relationships 32 1.6 The Need for Further Research into Anti-Cancer Drugs 32 r.7 Project Aims 55 Results and Discussion Chapter 2: (Aminoalkyl)carborane Ligands and Their Platinum(Il) Complexes 35 2.1 The(Aminoalkyl)carboraneLigands 36 2.1 .l Synthesis of 1-(Aminoalkyl)- 1,2-carborane Ligands 38 2.1.2 Synthesis of 1 -(Aminoalkyl)-1,7-carborane Ligands 43 2.1.2.1 Attempted Syntheses of I -(2-Phthalimidoethyl)- 1,7 - carbor ane 3 9, and 1 -(3 -Phthal imi dopropyl)- 1,7-carborane 40 44 2. I .2.2 Attempted Preparation of I - (3 -Hydroxypropyl) - 1,7-carborane 44 via a Silyl-Protected Intermediate 45 2.1.3 Attempted Mono-Alkylations of 7,7-Carborane 4 Without Prior Protection. 47 2.1 .3.1 Attempted Synthesis of I -(3 -Hydroxypropyl)- 1,7-carborane 44 V/ithout Prior Protection of 1,7-Carborane 4 47 2.1 .3.2 Attempted Synthesis of I -(2-Hydroxyethyl)- l,7-carborane 46 48 2.1 .3 .3 Attempted Synthesis of I -( I -Hydroxymethyl)- I,7-carborane 45 48 lll 2.1 .3 .4 Attempted Syntheses of I -(2-Hydroxyethyl-2- (t e r t-butyl-diphenylsilyl) ether)- 1,7-carborane 63 and I -(3-Hydroxypropyl-3- (terr-buryl- diphenylsilyl)- 1,7-carborane 64 49 2.1 .3.5 Attempted Synthesis of I -(4-Butylacetate)- 1,7-carborarrc 7l 52 2.1.4 Synthesis of a Hetero-Disubstituted 1,7-Carborane Ligand 53 2.1.4.1 Synthesis of I -(3-Iodopropyl)-7-(3-aminopropyl)- 1,7-carborane Hydrochloride 73 53 2.1.5 Synthesis of an (Aminoalkyl)-1,2-dicarba-nido- undecaborane Ligand 55 2.2 C¿s- and trans-fPtClz(NH¡)zl Derivatives Containing (Aminoalkyl)carborane Ligands 55 2.2.1 Attempted Syntheses of a Carborane-Containing Analogue of Cisplatin 55 2.2.l.lMethod 1- Adaptation of Dhara's Method. 55 2.2.1 .2 Metho d 2- Adaptati on of Kukushkin' s Method. 56 2.2.1.3 Attempted Syntheses of the Cisplatin Analogues 83 and 84 from [PtCl3NH3)]- 82(a or b) 57 2.2.I.4Investigation of pH-Dependence of the Reduction of Platinum(Il) Complexes to Elemental platinum by (Aminoalkyl)-1,2-carborane Ligands 23 and 24 63 2.2.1.5 Further Investigations into the Facto¡s Controlling the Reduction of the Platinum Complexes by Carborane 6s IV 2.2.2 Preparation of Platinum(Il) Derivatives Containing Three Monodentate N-Donor Ligands 67 2.2.2.1 Characterisation of the Platinum(Il) Derivatives Containing Three Monodentate N-Donor Ligands 70 2.2.2.2 DNA-Binding Studies of the Platinum(Il) Derivatives Containing the (Aminoalkyl)- carborane Ligands 76 2.3 Summary 77 Chapter 3: (Thioalkyl)carborane Ligands and Their Platinum(Il) Complexes Including DNA Metallointercalators 79 3.1 Metallointercalators 79 3.2 DNAMetallointercalators 79 3.2.1 [Pt(terpy)Cl]* 96 - The First DNA Metallointercalator 80 3.2-2 Other Metallointercalators 81 3 .2.2.1 Platinum(Il) Intercalators 82 3.2.3 Platinum-Thiol Complexes Containing 1,2- and |,7-Carborane Ligands 84 3.3 (Thioalkyl)carboraneLigands 86 3.3.1 Synthesis ofthe (Thioalkyl)-1,2-carborane Ligands 87 3.3. 1 . 1 Synthesis of I -Sulfanylmethyl- 1,2-carborane 1 l0 87 3.3.1 .2 Synthesis of I -Sulfanylpropyl-carborane 112 88 3.3.1.3 Synthesis of 1-Sulfanylethyl-I,2-carborane l1l 90 3.3.2 Synthesis of a l-(Thioalkyl)-1,7-carborane Ligand 92 v 3 .3 .2.1 Synthesis of I -Sulfanylmethyl- 1,7 - carborane I 13 92 3.4 Platinum(Il) Thiol Complexes 94 3.4.1 Attempted Synthesis of [PICþ(SRXÌ.{H¡)]- (R:1 -SCH z-1,2-CzHB¡ 6H¡ 6 127 or l-SCHz-1,7-CzHB roHro 128) 95 3.4.2 Attempted Synthesis of Trans-lPtCl(SRXNH3)21 (R: 1,2- SCHzCzHB¡¡H¡o 129 or 1,7-CHzCzHB¡6H¡s 130) 96 3.4.3 Reactions Between [PtCl2(en)] 104 and Thiol Ligands 99 3.4.3.1 Synthesis of [PtCl(SRXen)] (RSH: 105, 110 or 113) 100 3.4.4 Reactions between [Pt(dien)Br]Br 142 and the Thiol Ligands t02 3 .4.4.1 Attempted Synthesis of [Pt(dienXSR)] OTf (RSH = 105, 110, and 113) 103 3.5 MetallointercalatorsContainingthe(Thioalkyl)carborane Ligands r04 3.5.1 Synthesis ofthe ((Thioalkyl)carborane)(terpyridine)- platinum(Il) Complexes 105 3.5.2 CharacterisationoftheTerpyridineplatinum(Il) Metallointercalators 106 3.5.2.1 Characterisation by N.M.R. Spectroscopy 107 3.5.2.2 Characterisation ofthe Terpyridineplatinum(Il) Complexes by ESIMS 111 3.5.3 Other Metallointercalator Complexes ll6 vl 3.5.3.1 Characterisation of the Phen and Bipy Complexes 150 - 153 1t7 3.5.3.2 Molecular Structure of a Thiolato-Carborane Platinum(Il) Complex 119 3.6 Dimerisation Studies 121 J.t DNA Binding Studies of Metallointercalators 122 3.7.I Preliminary Results of DNA-Intercalation for Selected Carborane-Containing Terpyridineplatinum(Il) Complexes 143 - 147 r23 3.8 Summary 129 Conclusions and Future Work 131 Chapter 4: Experimental 134 4.1 General r34 4.2 Materials and Methods 136 4.3 Synthesisof(Aminoalkyl)carboraneLigands t37 4.3.1 Monodentate 1,2-(Aminoalkyl)carborane Ligands r37 4.3.2 Synthesis of Hetero-disubstituted (Aminoalkyl)- 1,7 - dicarba- c I o s o -dodecaborane ligands 145 4.4 SynthesisofPlatinum(Il)-amineComplexes 147 4.4.1 C¿s- and Trans-fPtClz(NH¡)zl Derivatives Containing the (Aminoalkyl)carborane Ligands 147 4.5 Synthesisof(Thioalkyl)carboraneLigands 152 4.5.1 1-(Thioalkyl)-1,2-carborane Ligands 152 4.5.2 Synthesis of 1-(Thioalkyl)-1,7-carborane Ligands 158 vll 4.6 Synthesis of Metallointercalator Complexes 160 4.6.1 Preparation of Metallointercalator Complexes Containing 2,2' :6,2" -Terpyridine and I -(Thioalkyl)- 1,2- or I,7-Carborane Ligands. 160 4.6.2 Preparation of Metallointercalators Containing the 1,1O-Phenanthroline 98 or 2,2'-Bipyridine 100 Moiety and 1,7- or \,2-Carborane Ligands. 16s 4.7 DNA Intercalation Experiments 168 Appendix: Complete Bond Length and Angle Data for lPtX I -S-1,2-CzBroHr ¡)2(bipy)l r53 t69 References 178 vlll Acknowledgements Firstly, I thank my supervisor Dr Louis Rendina for his much appreciated advice, assistance and patience during the course of this work. I also thank Dr D. Caiazza for her valuable advice and assistance. Thank you to Frances, Susan, Doug, Michael and Bill for their assistance, friendly faces and humour. I am grateful to Dr Edward Tiekink for always being ready to look at my crystals in hope of getting that elusive structure, and also for offering support. I thank Wendy Holstein and Andrew McAnnoy for running the ESIMS. Thank you Phil for assistance with the n.m.r. Thank you Oska for advice on UV - vis spectroscopy. I thank Dr Simon Pyke for his advice on 2D n.m.r. I would like to thank all those who were close to me during my PhD including Frank, Sonya and Frances. To Scott and Peter- thank you for being interested in my work and for all yotrr support and encouragement. In particular, I wish to express my gratitude to my family for supporting, consoling, and encouraging me all these years. "Although the universe is under no obligation to make sense, students in pursuit of the PhD. are." Robert P. Kirshner tx Abstract Boron Neutron Capture Therapy is a unique and rapidly developing area of anti-cancer research. The successful treatment of tumours refractory to all conventional forms of cancer therapy has created much interest in the field. However, BNCT is currently limited by a lack of suitable target compounds and the synthesis of new classes of compounds with potential use in BNCT is of great importance.