PHOSPHINEGOLD(I) THIOLATES: SYNTHESIS AND BIOLOGICAL ACTIVITIES PRIMJIRA TADBUPPA NATIONAL UNIVERSITY OF SINGAPORE 2009 PHOSPHINEGOLD(I) THIOLATES: SYNTHESIS AND BIOLOGICAL ACTIVITIES PRIMJIRA TADBUPPA (MSC., UNIVERSITY OF MANCHESTER) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF PHARMACY NATIONAL UNIVERSITY OF SINGAPORE 2009 Acknowledgements Acknowledgements First, I thank my supervisors A/P Edward R.T. Tiekink for his supervision from 2003-2005 and A/P Ho Chi Lui, Paul from 2005 onwards for their support in my study. A/P Tiekink has given me his guidance throughout the period I was under his supervision. A/P Ho has always been very kind, approachable and understanding throughout this period. He has never failed to follow up with me everynow and then. He encourages me to complete the study despite of my busy schedule. Without his encouragement and constant care I would not have accomplished my study. I also thank my company, GlaxoSmithKline for their financial and information support throughout my study. I would like to also thank my then fellow graduates in the laboratory for their friendship and support, particularly Dr Ho Soo Yei, Mr Lai Chian Sing, Dr Kuan Fong Sheen, Dr Ong Pei Shi and Dr Wu Jinzu. Last but not least, I thank my family for their continuing support and encouragement, particulary my husband for his love, understanding and help throughout this period. i Table of Content Table of Contents Summary I List of Tables II List of Figures . IV List of Schemes X List of Abbreviations XI Chapter Introduction 1.1 The physical and chemical properties of gold 1.1.1 1.1.2 1.1.3 1.2 Physical properties of the element Chemical reactivity of the element . Coordination chemistry of gold and gold complexes . Medicinal Chemistry of Gold Compounds . 13 1.2.1 1.2.2 1.2.2.1 1.2.2.2 1.2.2.3 1.2.2.4 1.2.3 1.3 Pharmacological potential of gold complexes 26 1.3.1 1.3.2 1.4 Historical use of gold in medicine 13 Gold complexes in the treatment of rheumatoid arthritis (RA) 14 Pharmacokinetic of gold compounds 15 Mechanism of action of gold complexes 17 Clinical Treatment with gold compound for RA patients . 21 Adverse effect of gold compound . 21 Gold complexes in other potential clinical application . 22 Cancer . 26 Gold complexes in the treatment of cancer . 26 Statement of Purpose 35 Chapter Experimental Procedures 37 2.1 Introduction . 38 2.2 Chemicals 38 2.3 Synthesis of ligands 39 2.3.1 2.3.2 2.4 Synthesis of O-alkyl, N-aryl thiocarbamate ligands, S=C(OR’)N(H)Ar 39 Synthesis of O-alkyl, N-alkyl thiocarbamate ligands, S=C(OR’)N(H)R’’40 Synthesis of gold chloride precursors . 42 2.4.1 2.5 Triorganophosphinegold(I) chlorides, R3PAuCl (R = Ph, Cy and Et) 42 Synthesis of targeted phosphinegold(I) thiolates 43 Chapter Characterization . 48 3.1 Introduction . 49 3.2 Instrumentation . 49 3.2.1 3.2.2 Infrared spectroscopy 49 Nuclear Magnetic Resonance (NMR) . 49 Phosphinegold(I) Thiolates: Synthesis and Biological Activities ii Table of Content 3.2.3 3.2.4 3.2.5 3.2.6 3.3 Mass spectrometry 49 Microanalysis 49 Melting point . 50 Crystallography . 50 Characterisation 50 3.3.1 Physical data of triorganophosphinegold(I) chlorides 50 3.3.2 Characterisation of Thiocarbamate Ligands . 51 3.3.3 Characterisation of Phosphinegold(I) Thiolates . 53 Chapter Biological Activity Studies 56 4.1 Introduction . 57 4.2 Biological studies of Phosphinegold(I) thiolates in cancer cell lines . 58 4.3 Procedures and Analysis . 60 4.4 Results and Discussion . 62 4.5 Conclusion 84 Chapter Calculation Of Descriptors . 85 5.1 Introduction . 86 5.2 Calculation of LogP and LogD using Marvin software 90 Chapter Correlation Of Descriptors And Biological Activity . 93 6.1 Introduction . 94 6.2 Correlation of Descriptors and biological activity 95 6.3 Discussion . 95 Chapter Final Conclusions And Proposed Future Studies . 97 7.1 Final Conclusions 98 7.2 Proposed Future Studies . 99 Bibliography . 100 Publications . 112 Appendices 114 Phosphinegold(I) Thiolates: Synthesis and Biological Activities iii Summary Summary The interest in phosphinegold(I) thiolates as an anti-cancer agent developed as a result of the previous discovery of cytotoxicity of phosphinegold(I) thiolates. A series of thiocarbamate ligands and its corresponding novel phosphinegold(I) thiolate were successfully synthesized and characterized. The compounds’ structure was confirmed by elemental analysis and X-ray crystallography. Biological evaluation of the synthesised thiocarbamate ligands and Phosphinegold(I) thiolates were performed on a range of human cancer cell lines and normal human fiboblast for cytotoxicity study. A positive biological activity was achieved for the Phosphinegold(I) thiolates at high concentration of 20 micromolar. Phosphinegold(I) thiolates were found to be more cytotoxic as compared to the thiocarbamate ligands at the same concentration, indicating the importance of the phosphine gold(I) function of the molecule. Descriptors such as logP, logD, polariability, PSA and the refractivity of the gold(I) complexes and its ligands were predicted using a computer software, Marvin. The descriptors were used to attempt the study of the structure-activity relationship. Although the compounds’ cytotoxicity were observed on the range of cancer cell lines but the structure activity relationship of the complexes was not established. There was little correlation between the activity and the descriptors’ value observed. Phosphinegold(I) Thiolates: Synthesis and Biological Activities I List of Tables List of Tables Table Comparative properties of Gold and some similarly grouped elements in the group . Table Chemical data and their sources 38 Table Basic physical data of the Thiocarbamate ligands . 40 Table Physical data triorganophosphinegold(I) chlorides . 43 Table Physical data for the Phosphinegold(I) thiolates . 44 Table Physical data of novel triorganophosphinegold(I) chlorides . 51 Table IR and Elemental Analysis of the phosphinegold(I) chlorides 51 Table Cancer cell lines and human fibroblast 59 Table Twenty Promising Phosphinegold(I) Thiolates . 83 Table 10 Physical and analytical data for thiocarbamate ligands 118 Table 11 IR data of the thiocarbamate Ligands . 120 Table 12 Table 13 13 Table 14 Physical and analytical data of Phosphinegold(I) thiolates 128 Table 15 IR data for phosphinegold(I) thiolates 134 Table 16 Table 17 13 Table 18 Descriptors for thiocarbamate ligands using Marvin Software calculator 187 Table 19 Descriptors for phosphinegold(I) thiolates using Marvin Software calculator 189 Table 20 The summary of R2 the correlation value of logP and biological activity of phosphinegold(I) thiolate on all cell lines at two concentrations. . 195 H NMR for Thiocarbamate Ligands 122 C{1H} NMR for Thiocarbamate ligands 125 H NMR for Phosphinegold(I) thiolates . 138 C{1H} and 31P{1H} NMR for Phosphinegold(I) thiolates . 146 Phosphinegold(I) Thiolates: Synthesis and Biological Activities II List of Tables Table 21 The summary of R2 the correlation value of logD and biological activity of phosphinegold(I) thiolate on all cell lines at two concentrations. . 195 Table 22 The summary of R2 the correlation value of Polarisability and biological activity of phosphinegold(I) thiolate on all cell lines at two concentrations. 195 Table 23 The summary of R2 the correlation value of Polar surface area and biological activity of phosphinegold(I) thiolate on all cell lines at two concentrations. 196 Table 24 The summary of R2 the correlation value of refractivity and biological activity of phosphinegold(I) thiolate on all cell lines at two concentrations. 196 Table 25 The summary of R2 the correlation value of LogP and biological activity of thiocarbamate ligands on all cell lines at two concentrations 196 Table 26 The summary of R2 the correlation value of LogD and biological activity of thiocarbamate ligands on all cell lines at two concentrations 197 Table 27 The summary of R2 the correlation value of Polarisability and biological activity of thiocarbamate ligands on all cell lines at two concentrations 197 Table 28 The summary of R2 the correlation value of polar surface area and biological activity of thiocarbamate ligands on all cell lines at two concentrations 197 Table 29 The summary of R2 the correlation value of polar surface area and biological activity of thiocarbamate ligands on all cell lines at two concentrations 198 Phosphinegold(I) Thiolates: Synthesis and Biological Activities III List of Figures List of Figures Figure Examples of gold (I) complexes [C3H7NCAuCl] with linear geometry Figure Examples of gold (I) complexes with higher coordinate complexes (2) [(TPA)3Au)2Au2(S2C2(CN)2)2] (3) - [Au(S2CPh)(PPh3)2] . 10 Figure Structures of di and tri nuclear gold (II) complexes with a gold-gold bond a) binuclear complex, b) trinuclear complex . 11 Figure Structure of a square planar four coordinate gold(II) centre,27 11 Figure Structure of a Octahedral coordinate gold(II) centre, [Au-(II)Hp-2H.(H2O)2] 12 Figure Structure of square pyramidal coordinate gold(III) centre, [AuCl(CllH8N30)2].H20]. 13 Figure Chemical structures for aurothioglucose (9), di-sodium aurothiomalate (10), tri-sodium salt of bis(thiosulfato)gold (11), aurothiopropanol sulphonate (12), gold(I) 4-amino-2-mercaptobenzoate (13) and [tetra-O-acetyl-β-D(glucopyranosyl)thio]- (triethylphosphinegold) . 16 Figure Metabolic Pathway of gold drugs 20 Figure Thiol-shuttle Model (CSH refers to cytosolic thiols, protein or low molecular weight thiols) 21 Figure 10 Chemical structures of gold(III) salicylate complex (15), gold(III) thiosalicylate complex (16) and 2-benzylpyridylgold(III) catecholate (17) 23 Figure 11 Chemical structures 60 of [Ph3PAu(chloroquine)]PF6 . 24 Figure 12 Chemical structure of cationic [Au(dppe)2]+ (19) . 28 Figure 13 Chemical structures of gold complexes Chlorotriphenylphosphine-1,3bis(diphenylphosphino)propanegold(I) (20) and Chlorotetrakis((trishydroxymethyl) phosphine)gold(I) (21) 29 Figure 14 Example of Chemical structures of gold-carbine complexes (22) 30 Figure 15 Chemical structures of gold (I) complexes Ph3PAu(6-MP) (23), Et3PAu(S2CNEt2) (24) and Vitamin K derivatives (25) 32 Figure 16 Chemical structures of Dinuclear gold complex (26) and Neutral gold(III) compound (27), gold(III) meso-tetraarylporphyrins complexes (28) 35 Phosphinegold(I) Thiolates: Synthesis and Biological Activities IV List of Figures Figure 17 Labeling scheme for the thiolcarbamate ligands 52 Figure 18 Labeling scheme for the thiolates and phosphine ligands 55 Figure 19 Survival index of A-498 cell line against thiocarbamate ligands . 66 Figure 20 Survival index of Hela cell line against thiocarbamate ligands 66 Figure 21 Survival index of HT29 cell line against thiocarbamate ligands 67 Figure 22 Survival index of NCI cell line against thiocarbamate ligands . 67 Figure 23 Survival index of HepG2 cell line against thiocarbamate ligands 68 Figure 24 Survival index of MCF7 cell line against thiocarbamate ligands . 68 Figure 25 Survival index of OVCAR3 cell line against thiocarbamate ligands . 69 Figure 26 Survival index of HF against thiocarbamate ligands 69 Figure 27 Survival index of A-498 cell line against phosphinegold(I) thilates 70 Figure 28 Survival index of Hela cell line against phosphinegold(I) thiolates . 70 Figure 29 Survival index of HT29 cell line against phosphinegold(I) thiolates . 71 Figure 30 Survival index of NCI cell line against phosphinegold(I) thiolates 71 Figure 31 Survival index of HepG2 cell line against phosphinegold(I) thiolates . 72 Figure 32 Survival index of MCF7 cell line against phosphinegold(I) thiolates 72 Figure 33 Survival index of OVCAR3 cell line against phosphinegold(I) thiolates . 73 Figure 34 Survival index of HF against phosphinegold(I) thiolates . 73 Figure 35 Average survival index of all cell lines against thiocarbamate ligands 74 Figure 36 Average survival index of all cell lines against phosphinegold(I) thiolates . 74 Figure 37 Cytotoxicity of Thiocarbamate ligands on A-498 cell line 75 Figure 38 Cytotoxicity of Thiocarbamate ligands on Hela cell line 75 Figure 39 Cytotoxicity of Thiocarbamate ligands on HT29 cell line . 76 Figure 40 Cytotoxicity of Thiocarbamate ligands on NCI cell line . 76 Figure 41 Cytotoxicity of Thiocarbamate ligands on HepG2 cell line 77 Phosphinegold(I) Thiolates: Synthesis and Biological Activities V Appendix Table 26 The summary of R2 the correlation value of LogD and biological activity of thiocarbamate ligands on all cell lines at two concentrations Cell Lines A498 Hela HepG2 HT29 MCF7 NCI OVCAR3 R2 (High Concentration) 0.0056 0.1114 0.0632 0.1663 0.0376 0.0066 0.014 R2 (Low Concentration) 0.2055 0.2268 0.037 0.1227 0.1115 0.006 0.0069 Table 27 The summary of R2 the correlation value of Polarisability and biological activity of thiocarbamate ligands on all cell lines at two concentrations Cell Lines A498 Hela HepG2 HT29 MCF7 NCI OVCAR3 R2 (High Concentration) 0.0042 0.1203 0.0743 0.1547 4.67E-02 0.0057 0.0133 R2 (Low Concentration) 0.1721 0.1842 0.0215 0.0928 0.0833 0.0024 0.0023 Table 28 The summary of R2 the correlation value of polar surface area and biological activity of thiocarbamate ligands on all cell lines at two concentrations Cell Lines A498 Hela HepG2 HT29 MCF7 NCI OVCAR3 R2 (High Concentration) 3.00E-15 6.00E-15 4.00E-15 3.00E-14 7.00E-15 8.00E-15 1.00E-15 Phosphinegold(I) Thiolates: Synthesis and Biological Activities R2 (Low Concentration) 3.00E-15 2.00E-15 2.00E-14 1.00E-15 1.00E-14 197 Appendix Table 29 The summary of R2 the correlation value of polar surface area and biological activity of thiocarbamate ligands on all cell lines at two concentrations Cell Lines A498 Hela HepG2 HT29 MCF7 NCI OVCAR3 R2 (High Concentration) 0.0038 0.116 0.0668 0.1578 3.93E-02 0.0059 0.0109 Phosphinegold(I) Thiolates: Synthesis and Biological Activities R2 (Low Concentration) 0.1881 0.2055 0.0272 0.1127 0.0956 0.0033 0.0034 198 Appendix Figure 83 The correlation of descriptors and the biological activity of Thiocarbamate ligands on A498 cancer cell at high concentration Figure 84 The correlation of descriptors and the biological activity of Thiocarbamate ligands on A498 cancer cell at low concentration Phosphinegold(I) Thiolates: Synthesis and Biological Activities 199 Appendix Figure 85 The correlation of descriptors and the biological activity of Thiocarbamate ligands on Hela cancer cell at high concentration Figure 86 The correlation of descriptors and the biological activity of Thiocarbamate ligands on Hela cancer cell at low concentration Phosphinegold(I) Thiolates: Synthesis and Biological Activities 200 Appendix Figure 87 The correlation of descriptors and the biological activity of Thiocarbamate ligands on HepG2 cancer cell at high concentration Figure 88 The correlation of descriptors and the biological activity of Thiocarbamate ligands on HepG2 cancer cell at low concentration Phosphinegold(I) Thiolates: Synthesis and Biological Activities 201 Appendix Figure 89 The correlation of descriptors and the biological activity of Thiocarbamate ligands on HT29 cancer cell at high concentration Figure 90 The correlation of descriptors and the biological activity of Thiocarbamate ligands on HT29 cancer cell at low concentration Phosphinegold(I) Thiolates: Synthesis and Biological Activities 202 Appendix Figure 91 The correlation of descriptors and the biological activity of Thiocarbamate ligands on MCF7 cancer cell at high concentration Figure 92 The correlation of descriptors and the biological activity of Thiocarbamate ligands on MCF7 cancer cell at low concentration Phosphinegold(I) Thiolates: Synthesis and Biological Activities 203 Appendix Figure 93 The correlation of descriptors and the biological activity of Thiocarbamate ligands on NCI cancer cell at high concentration Figure 94 The correlation of descriptors and the biological activity of Thiocarbamate ligands on NCI cancer cell at low concentration Phosphinegold(I) Thiolates: Synthesis and Biological Activities 204 Appendix Figure 95 The correlation of descriptors and the biological activity of Thiocarbamate ligands on OVCAR3 cancer cell at high concentration Figure 96 The correlation of descriptors and the biological activity of Thiocarbamate ligands on OVCAR3 cancer cell at low concentration Phosphinegold(I) Thiolates: Synthesis and Biological Activities 205 Appendix MVA_PrimWork.M1 (PLS) YPred[Last comp.](A-498(H) activity)/YVar(A-498(H) activity) 60 y=1*x-8.653e-007 R2=0.1916 YVar(A-498(H) activity) 50 40 30 20 10 10 20 30 40 50 60 YPred[4](A-498(H) activity) RMSEE = 13.1078 SIMCA-P+ 11 - 13/10/2009 1:54:06 PM Figure 97 The correlation of descriptors and the biological activity of Phosphinegold(I) Thiolates on A498 cancer cell at high concentration MVA_PrimWork.M1 (PLS) YPred[Last comp.](A-498(L) activity)/YVar(A-498(L) activity) 2.0 y=1*x-5.722e-008 R2=0.1438 1.8 YVar(A-498(L) activity) 1.6 1.4 1.2 1.0 0.8 0.6 0.4 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 2.0 YPred[4](A-498(L) activity) RMSEE = 0.35252 SIMCA-P+ 11 - 13/10/2009 1:54:21 PM Figure 98 The correlation of descriptors and the biological activity of Phosphinegold(I) Thiolates on A498 cancer cell at low concentration Phosphinegold(I) Thiolates: Synthesis and Biological Activities 206 Appendix MVA_PrimWork.M1 (PLS) YPred[Last comp.](HeLa(H) activity)/YVar(HeLa(H) activity) 140 y=1*x-5.447e-007 R2=0.1025 120 YVar(HeLa(H) activity) 100 80 60 40 20 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 YPred[4](HeLa(H) activity) RMSEE = 21.7573 SIMCA-P+ 11 - 13/10/2009 2:00:08 PM Figure 99 The correlation of descriptors and the biological activity of Phosphinegold(I) Thiolates on Hela cancer cell at high concentration MVA_PrimWork.M1 (PLS) YPred[Last comp.](HeLa(L) activity)/YVar(HeLa(L) activity) 1.4 y=1*x-8.367e-009 R2=0.1074 1.3 YVar(HeLa(L) activity) 1.2 1.1 1.0 0.9 0.8 0.7 0.6 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4 YPred[4](HeLa(L) activity) RMSEE = 0.179414 SIMCA-P+ 11 - 13/10/2009 2:00:23 PM Figure 100 The correlation of descriptors and the biological activity of Phosphinegold(I) Thiolates on Hela cancer cell at low concentration Phosphinegold(I) Thiolates: Synthesis and Biological Activities 207 Appendix MVA_PrimWork.M1 (PLS) YPred[Last comp.](HepG2(H) activity)/YVar(HepG2(H) activity) 18 y=1*x-2.894e-007 R2=0.239 16 YVar(HepG2(H) activity) 14 12 10 0 10 11 12 13 14 15 16 17 18 YPred[4](HepG2(H) activity) RMSEE = 3.7388 SIMCA-P+ 11 - 13/10/2009 1:55:09 PM Figure 101 The correlation of descriptors and the biological activity of Phosphinegold(I) Thiolates on HepG2 cancer cell at high concentration MVA_PrimWork.M1 (PLS) YPred[Last comp.](HepG2(L) activity)/YVar(HepG2(L) activity) y=1*x+4.048e-007 R2=0.04545 1.3 YVar(HepG2(L) activity) 1.2 1.1 1.0 0.9 0.8 0.7 0.6 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 YPred[4](HepG2(L) activity) RMSEE = 0.167339 SIMCA-P+ 11 - 13/10/2009 1:55:26 PM Figure 102 The correlation of descriptors and the biological activity of Phosphinegold(I) Thiolates on HepG2 cancer cell at low concentration Phosphinegold(I) Thiolates: Synthesis and Biological Activities 208 Appendix MVA_PrimWork.M1 (PLS) YPred[Last comp.](HT29(H) activity)/YVar(HT29(H) activity) 140 y=1*x-8.499e-007 R2=0.2275 120 YVar(HT29(H) activity) 100 80 60 40 20 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 YPred[4](HT29(H) activity) RMSEE = 19.0978 SIMCA-P+ 11 - 13/10/2009 1:54:37 PM Figure 103 The correlation of descriptors and the biological activity of Phosphinegold(I) Thiolates on HT29 cancer cell at high concentration MVA_PrimWork.M1 (PLS) YPred[Last comp.](HT29(L) activity)/YVar(HT29(L) activity) 11 y=1*x-3.94e-007 R2=0.3357 10 YVar(HT29(L) activity) 10 11 YPred[4](HT29(L) activity) RMSEE = 3.08129 SIMCA-P+ 11 - 13/10/2009 1:54:52 PM Figure 104 The correlation of descriptors and the biological activity of Phosphinegold(I) Thiolates on HT29 cancer cell at low concentration Phosphinegold(I) Thiolates: Synthesis and Biological Activities 209 Appendix MVA_PrimWork.M1 (PLS) YPred[Last comp.](MCF7(H) activty)/YVar(MCF7(H) activty) 60 y=1*x-3.134e-007 R2=0.138 YVar(MCF7(H) activty) 50 40 30 20 10 0 10 20 30 40 50 60 YPred[4](MCF7(H) activty) RMSEE = 10.1071 SIMCA-P+ 11 - 13/10/2009 1:55:45 PM Figure 105 The correlation of descriptors and the biological activity of Phosphinegold(I) Thiolates on MCF7 cancer cell at high concentration MVA_PrimWork.M1 (PLS) YPred[Last comp.](MCF7(L) activity)/YVar(MCF7(L) activity) 1.2 y=1*x+6.122e-008 R2=0.09151 1.1 YVar(MCF7(L) activity) 1.0 0.9 0.8 0.7 0.6 0.5 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 YPred[4](MCF7(L) activity) RMSEE = 0.155017 SIMCA-P+ 11 - 13/10/2009 1:56:00 PM Figure 106 The correlation of descriptors and the biological activity of Phosphinegold(I) Thiolates on MCF7 cancer cell at low concentration Phosphinegold(I) Thiolates: Synthesis and Biological Activities 210 Appendix MVA_PrimWork.M1 (PLS) YPred[Last comp.](NCI(H) activity)/YVar(NCI(H) activity) 180 y=1*x-2.766e-006 R2=0.2507 160 140 YVar(NCI(H) activ ity ) 120 100 80 60 40 20 -10 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 YPred[4](NCI(H) activity) RMSEE = 37.4566 SIMCA-P+ 11 - 13/10/2009 1:59:05 PM Figure 107 The correlation of descriptors and the biological activity of Phosphinegold(I) Thiolates on NCI cancer cell at high concentration MVA_PrimWork.M1 (PLS) YPred[Last comp.](NCI(L) activity)/YVar(NCI(L) activity) 1.3 y=1*x-1.98e-007 R2=0.04081 1.2 YVar(NCI(L) activity) 1.1 1.0 0.9 0.8 0.7 0.6 0.5 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 YPred[4](NCI(L) activity) RMSEE = 0.193394 SIMCA-P+ 11 - 13/10/2009 1:59:17 PM Figure 108 The correlation of descriptors and the biological activity of Phosphinegold(I) Thiolates on NCI cancer cell at low concentration Phosphinegold(I) Thiolates: Synthesis and Biological Activities 211 Appendix MVA_PrimWork.M1 (PLS) YPred[Last comp.](OVCAR3(H) activity)/YVar(OVCAR3(H) activity) y=1*x-5.548e-007 R2=0.3718 YVar(OVCAR3(H) activity) 40 30 20 10 10 20 30 40 YPred[4](OVCAR3(H) activity) RMSEE = 9.26962 SIMCA-P+ 11 - 13/10/2009 1:59:37 PM Figure 109 The correlation of descriptors and the biological activity of Phosphinegold(I) Thiolates on OVCAR3 cancer cell at high concentration MVA_PrimWork.M1 (PLS) YPred[Last comp.](OVCAR3(L) activity)/YVar(OVCAR3(L) activity) 1.7 y=1*x-9.419e-008 R2=0.09427 1.6 1.5 YVar(O VCAR3(L) activity) 1.4 1.3 1.2 1.1 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 YPred[4](OVCAR3(L) activity) RMSEE = 0.225037 SIMCA-P+ 11 - 13/10/2009 1:59:50 PM Figure 110 The correlation of descriptors and the biological activity of Phosphinegold(I) Thiolates on OVCAR3 cancer cell at low concentration Phosphinegold(I) Thiolates: Synthesis and Biological Activities 212 [...]... descriptors and the biological activity of Phosphinegold(I) Thiolates on HT29 cancer cell at high concentration 209 Figure 104 The correlation of descriptors and the biological activity of Phosphinegold(I) Thiolates on HT29 cancer cell at low concentration 209 Phosphinegold(I) Thiolates: Synthesis and Biological Activities VIII List of Figures Figure 105 The correlation of descriptors and the biological. .. no of molecules in the assymetric unit Phosphinegold(I) Thiolates: Synthesis and Biological Activities XV Chapter 1 Introduction Phosphinegold(I) Thiolates: Synthesis and Biological Activities 1 Chapter 1 Introduction 1.1 The physical and chemical properties of gold Gold is one of the best known precious metals for use as jewellery, a medium of monetary exchange and investment Gold has long been viewed... The correlation of descriptors and the biological activity of Phosphinegold(I) Thiolates on Hela cancer cell at low concentration 207 Figure 101 The correlation of descriptors and the biological activity of Phosphinegold(I) Thiolates on HepG2 cancer cell at high concentration 208 Figure 102 The correlation of descriptors and the biological activity of Phosphinegold(I) Thiolates on HepG2 cancer cell... Phosphinegold(I) Thiolates: Synthesis and Biological Activities VII List of Figures Figure 89 The correlation of descriptors and the biological activity of Thiocarbamate ligands on HT29 cancer cell at high concentration 202 Figure 90 The correlation of descriptors and the biological activity of Thiocarbamate ligands on HT29 cancer cell at low concentration 202 Figure 91 The correlation of descriptors and. .. correlation of descriptors and the biological activity of Phosphinegold(I) Thiolates on NCI cancer cell at low concentration 211 Figure 109 The correlation of descriptors and the biological activity of Phosphinegold(I) Thiolates on OVCAR3 cancer cell at high concentration 212 Figure 110 The correlation of descriptors and the biological activity of Phosphinegold(I) Thiolates on OVCAR3 cancer... The correlation of descriptors and the biological activity of Phosphinegold(I) Thiolates on A498 cancer cell at high concentration 206 Figure 98 The correlation of descriptors and the biological activity of Phosphinegold(I) Thiolates on A498 cancer cell at low concentration 206 Figure 99 The correlation of descriptors and the biological activity of Phosphinegold(I) Thiolates on Hela cancer cell at... of descriptors and the biological activity of Phosphinegold(I) Thiolates on MCF7 cancer cell at high concentration 210 Figure 106 The correlation of descriptors and the biological activity of Phosphinegold(I) Thiolates on MCF7 cancer cell at low concentration 210 Figure 107 The correlation of descriptors and the biological activity of Phosphinegold(I) Thiolates on NCI cancer cell at high concentration... Thiocarbamate ligands on MCF7 cell line 77 Figure 43 Cytotoxicity of Thiocarbamate ligands on OVCAR3 cell line 78 Figure 44 Cytotoxicity of Phosphinegold(I) Thiolates on A-498 cell line 78 Figure 45 Cytotoxicity of Phosphinegold(I) Thiolates on Hela cell line 79 Figure 46 Cytotoxicity of Phosphinegold(I) Thiolates on HT29 cell line 79 Figure 47 Cytotoxicity of Phosphinegold(I) Thiolates on... concentration 212 Phosphinegold(I) Thiolates: Synthesis and Biological Activities IX List of Abbreviations List of Schemes Scheme 1 Preparation of S=C(OR′)N(H)Ar 40 Scheme 2 Preparation of S=C(OR’)N(H)R” 40 Scheme 3 Preparation of mononuclear triorganophosphinegold(I) chlorides 42 Scheme 4 Synthesis of targeted triorganophosphinegold(I) thiolates 44 Scheme 5 Definition... descriptors and the biological activity of Thiocarbamate ligands on Hela cancer cell at low concentration 200 Figure 87 The correlation of descriptors and the biological activity of Thiocarbamate ligands on HepG2 cancer cell at high concentration 201 Figure 88 The correlation of descriptors and the biological activity of Thiocarbamate ligands on HepG2 cancer cell at low concentration 201 Phosphinegold(I) . Phosphinegold(I) Thiolates: Synthesis and Biological Activities V Figure 17 Labeling scheme for the thiolcarbamate ligands 52 Figure 18 Labeling scheme for the thiolates and phosphine ligands. List of Figures Phosphinegold(I) Thiolates: Synthesis and Biological Activities IX Figure 105 The correlation of descriptors and the biological activity of Phosphinegold(I) Thiolates on MCF7. encouragement, particulary my husband for his love, understanding and help throughout this period. Table of Content Phosphinegold(I) Thiolates: Synthesis and Biological Activities ii Table of