Tuning Reactivity of Platinum(II) Complexes

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transformational pathways that compete for the bioavailability of the drug at the target, DNA (Figure 1.5). Figure 1.5: Schematic pathway of a platinum drug in cells showing how sulphur containing compounds are thought to act as potential drug reserving agents in platinum chemotherapy. 51 Inside the cell, the active forms of the drug, i.e. Cl/H2O (1) and H2O/H2O (2), do not only undergo DNA (N-donor) adduct formation, but also can be deactivated by S-donor biomolecules such as glutathione (0.5-10 mM GSH) and metallothioneins (MT) that are available in large amounts. 52 This results in accumulation of Pt-S intermediates in vivo that depletes intracellular concentration of the drug to levels insufficient to inhibit tumour growth and is responsible for the serious toxic side effects of cisplatin caused by binding of platinum to the proteins. 10,49,53, The high affinity of sulphur for Pt(II) centre has led to the development of the so-called “rescue or protective agents” like thiourea (TU), 2-mercaptoethanesulfonate (mesna) and sodium thiosulphate (STS). These are co- administered with other drugs to suppress the coordination of platinum to S-containing proteins which is responsible for severe toxic side effects such as nephrotoxicity (reduced kidney function and damage), ototoxicity (hearing loss) and myelosuppression (reduction in bone marrow activity). 49,54 Their protective effect can be attributed to either prevention from causing unwanted toxic side effects 49,55 or reversals of the Pt-S 9
adducts in proteins and therefore act as platinum-reservoirs. Finally, the remaining platinum compounds probably are excreted from the cell via the Golgi apparatus, a process that also brings about cell detoxification. 56,57 1.3.3 New and “Non-classical” Platinum Complexes In an effort to overcome the resistance and reduce the toxicity of cisplatin, novel platinum complexes have been designed and synthesised. These include “second generation platinum drugs” with improved toxicological profiles and “third generation drugs” that have the advantages of overcoming cisplatin resistance and convenience of drug delivery and administration. 1.3.3.1 Second Generation Cisplatin Analogues Carboplatin (cis-diammine-1,1’-cyclobutanedicarboxylatoplatinate(II)) was developed on the hypothesis that altering the leaving group could change the toxicity of the platinum drug. As an example of the second generation platinum anti-tumour compound, it still carries primary amines as the inert ligand and a more stable (1,1’- cyclobutanedicarboxylate) leaving group that slows down the hydrolytic activation. The cyclobutanedicarboxylate ligand confers a 17-fold increase in solubility in water and a moderate rate of hydrolysis (10 -8 s -1) compared to cisplatin (10 -5 s -1). 58,59 Such properties confer to the drug the following effects: longer circulation lifetime in the body due to its improved stability, reduced toxicity as a result of the decreased rate of competitive binding to plasma proteins, glutathione and other platinum deactivating biomolecules, due to lower reactivity, a higher dosage of up to 2000 mg d -1 can be administered. Carboplatin is successful in the treatment of ovarian cancer, but is unable to overcome cisplatin-acquired resistance. Oxaliplatin [oxalato-1,2-diaminocyclohexaneplatinum(II)] (figure 1.1) is most effective in the treatment of colon cancer, a type of cancer that is insensitive to cisplatin and carboplatin treatments. It was developed and first used as an anti-cancer drug in France in 1996. The oxalate leaving group enhances its aqueous solubility and also slows down 10
Page 1 and 2: Tuning Reactivity of Platinum(II) C
Page 3 and 4: Declaration This thesis report is b
Page 5 and 6: Abstract Systematic kinetic and the
Page 7 and 8: Table of contents Acknowledgements
Page 9 and 10: 2.5.5 Effect of Non-participating G
Page 11 and 12: 5.2.1 Chemical and Solutions ......
Page 13 and 14: 7.2 Experimental Section ..........
Page 15 and 16: procurements, Messers P. Forder and
Page 17 and 18: Figure 2.2 Potential energy profile
Page 19 and 20: Figure 4.6 Concentration dependence
Page 21 and 22: Figure 6.1 Spectrophotometric titra
Page 23 and 24: List of Tables Table 2.1 A selectio
Page 25 and 26: Table 6.4 Summary of rate constants
Page 27 and 28: TU thiourea DMTU 1,3-dimethyl-2-thi
Page 30 and 31: Table of Contents-1 Chapter 1 .....
Page 32 and 33: 1.0 Introduction 1.1 Cancer Disease
Page 34 and 35: toxic potential. The most well-know
Page 36 and 37: 1.3.2.2 Cellular Uptake Cisplatin i
Page 38 and 39: H 3N OH 2 Pt H 3N OH 2 Active Pt(II
Page 42 and 43: the hydrolysis of the complex, wher
Page 44 and 45: 1.3.4 Terpyridine Platinum(II) Comp
Page 46 and 47: H 3 N Cl Pt NH 3 H 3 N NH 2 (CH 2 )
Page 48 and 49: 1.4 Kinetic Interest The platinum-b
Page 50 and 51: 3. The effect of varying the positi
Page 52 and 53: 17 R. A. Henderson, The Mechanism o
Page 54 and 55: Altona J. H. van Boom, G. A. van de
Page 56 and 57: 76 (a)J. Kašpárková, J. Zehnulov
Page 58 and 59: Table of Contents-2 Chapter Two ...
Page 60 and 61: List of Tables Table 2.1: A selecti
Page 62 and 63: The mononuclear Pt(II) complexes 1-
Page 64 and 65: Potential Energy R + X RX 1 transit
Page 66 and 67: For the associative mechanism (A),
Page 68 and 69: the concentration of one of the rea
Page 70 and 71: k obs , s -1 0.00030 0.00025 0.0002
Page 72 and 73: k = Ae -Ea/RT 2.14 lnk = lnA - E a
Page 74 and 75: = 23.76 + R Hence, a plot of ln ⎛
Page 76 and 77: iii. # Δ V ≈ 10 cm3 mol-1 featur
Page 78 and 79: conventional methods are classical
Page 80 and 81: Figure 2.6: Schematic diagram of a
Page 82 and 83: The light transmitted from the samp
Page 84 and 85: c. Oxidizability: Ligands that are
Page 86 and 87: Table 2.1: A selection of n o pt va
Page 88 and 89: eaction with different nucleophiles
Page 90 and 91:
eaction site from direct attack by
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PEt 3 PEt 3 R PEt 3 Pt Pt Y Y Cl R
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direct displacement of the leaving
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therefore, weaken the bond of the l
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σ-Donation According to classical
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References 1 (a) J. Reedijk, Chem.
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34 R. B. Jordan, Reaction Mechanism
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Table of Contents-3 Chapter 3.The
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Chapter 3 The π-Acceptor Effect in
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In order to extend our understandin
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after which water was added to quen
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O CH 3 + I + N O oH - N O O 7 CH 3
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84% (34.7 mg, 0.0618 mmol). 1 H NMR
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PhCN PhCN Pt Cl Cl + N N CH 3 N CH
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Complex Structure HOMO LUMO PtCl CH
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The geometry-optimised structures i
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against the concentration of the in
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Table 3.2: Summary of the second-or
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constants of CH3PhisoqPtCl decrease
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with π*-orbitals of the ligand. Th
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3.6 References 1 D. Rosenberg, L. V
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30 Microcal TM Origin TM Version 5.
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Figure S3.1: Kinetic trace at 448 n
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ln(k 2 /T) -6.0 -7.5 -9.0 -10.5 -12
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Table S3.3b: Average observed rate
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Table S3.5b: Temperature dependence
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Table S3.8: DFT calculated electros
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List of Figures Figure 4.1: Structu
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Table 4.2: Summary of pKa values fo
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4.1 Introduction Platinum compounds
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cis geometry, leading to dramatic c
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ligand was added to the [{cis-PtCl(
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spectra were measured in and refere
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4.3.1 DFT calculated Optimized Stru
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Table 4.1: A summary of the DFT cal
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H2O-Pt-L-Pt-OH2 H2O-Pt-L-Pt-OH2 H2O
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electrophilicity and acidity of the
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(A) 18 Absorbance 0.08 0.07 0.06 0.
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k obs(3 rd ) , s -1 -5 6.00x10 TMTU
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4.3.4 Kinetics with NMR The substit
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ln([ML] t ) 4.0 3.5 3.0 2.5 2.0 1.5
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ln(k 2(1 st ) /T) -3.5 -4.0 -4.5 -5
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Comple x Table 4.4: Summary of Acti
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The decrease in reactivity of 2,6pz
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Table 4.5: DFT calculated (NBO) cha
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eaction proceeds via bimolecular pa
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References 1 T. Storr, K. H.Thomson
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36 D. Jaganyi, D. Reddy, J.A. Gerte
Page 186 and 187:
Appendix 4 THE INFLUENCE OF THE PYR
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Absorbance at 368. 0 nm 0. 0 8 0. 0
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Table S4.3: Average observed rate c
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k nd obs(2 ) , s-1 0.003 TU DMTU TM
Page 194 and 195:
Page 196 and 197:
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k obs2 , s -1 2.40x10 -4 2.20x10 -4
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Table S4.13: Average observed rate
Page 202 and 203:
Page 204 and 205:
Page 206 and 207:
k obs(1 st ) , s -1 0.06 0.04 0.02
Page 208 and 209:
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ln(k 2(3 rd ) /T) -10.0 -10.5 -11.0
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SpinWorks 2.5: 2,6 pznClO4 in D2O N
Page 214 and 215:
Table of Contents-5 Chapter 5 .....
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List of Tables Table 5.1: A summary
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5.1 Introduction Multinuclear plati
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onding. For this reason, pKa titrat
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400-300 cm -1): 3308, 3117, 3071 (N
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5.2.6 Spectrophotometric pKa Titrat
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Table 5.1: A summary of DFT-calcula
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However, because the highest occupi
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Table 5.2: Acid dissociation consta
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Table 5.3: A summary of DFT calcula
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H3N 6 eq TU 0 eq TU Ha NH3 Ha Cl TU
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third step due to the trans-effect
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[H 2 O-Pt-(NN)-Pt-OH 2 ] +4 [NU-Pt-
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k obs(1st) / s -1 0.20 TU DMTU TMTU
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thiourea nucleophile is large enoug
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ln(k st 2(1 ) /T) -3 -4 -5 -6 -7 -8
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is the same as the electron-withdra
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associative mode of substitution me
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16 H. Ertürk, J. Maigut, R. Puchta
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43 (a) D. Jaganyi, A. Hofmann and R
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276 nm Absorbance 0 . 6 5 0 . 6 4 0
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k obs(1 st ) , s -1 0.4 0.3 0.2 0.1
Page 258 and 259:
Page 260 and 261:
ln(k 2(2 nd ) /T) -8.0 TU -8.5 -9.0
Page 262 and 263:
pzn PPM -1750.0 -1850.0 -1950.0 -20
Page 264 and 265:
Page 266 and 267:
Figure S5.13: UV/Visible spectra fo
Page 268 and 269:
k obs(1 st ) in s -1 0.030 0.025 0.
Page 270 and 271:
Page 272 and 273:
ln(k 2(2 nd ) /T) -10 -11 -12 -13 -
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9.61 ppm Ha PPM 9.8 9.6 9.4 9.2 9.0
Page 276 and 277:
Page 278 and 279:
k obs(3rd) / s -1 -5 8 .00 x 10 T U
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ln(k st 2(1 ) /T) -1.5 TU DMTU TMTU
Page 282 and 283:
ln(k rd 2(3 ) /T) -8.5 -9.0 -9.5 -1
Page 284 and 285:
SpinWorks 2.5: znPt(II)-OP4 in D2O
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Figure S5.31: Mass spectrum for com
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Page 290 and 291:
Page 292 and 293:
ln(k st 2(1 ) /T) -4 -5 -6 -7 -8 -9
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SpinWorks 2.5: phtPt(II)-OP2 in D2O
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Figure S5.41: Mass spectrum for com
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List of Figures Figure 6.1: Spectro
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Chapter 6 Tuning Reactivity of Plat
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Against this background, several re
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6.2.2 Instruments Microanalyses wer
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Metal Complex Pt3 Yield: 52.5 mg (0
Page 308 and 309:
6.3 Results 6.3.1 Synthesis and Cha
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The pKa values obtained are summari
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Table 6.2: DFT-calculated parameter
Page 314 and 315:
that of dinuclear Pt(II) complexes
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It can be concluded that substituti
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ate constants, kobs(1 st /2 nd ), w
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Table 6.3: Summary of rate constant
Page 322 and 323:
6.3.6 Activation Parameters The act
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pKa1 values become smaller. In addi
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of steric influence is felt by the
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6.5 Conclusion The present study ha
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17 O. F. Wendt and L. I. Elding, 19
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51 Y. Iwadata, K. Kawamura, K. Igar
Page 334 and 335:
Page 336 and 337:
Table S6.4(b): Average observed rat
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ln(k 2(2 nd ) /T) -4 -6 -8 -10 -12
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45.0 40 35 30 25 20 %T 15 10 5 0 -5
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k st obs(1 ) in s-1 0.30 Br TU 0.25
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Page 346 and 347:
-2304.16 ppm H 3N PPM -2200.0 -2220
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Page 350 and 351:
Page 352 and 353:
Absorbance 1.6 1.4 1.2 1.0 0.8 0.6
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SH N SH + Mechanism Br N + CO 3 2-
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Figure 7.5: 195Pt NMR spectra of mi
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linker remained coordinated to the
Page 360 and 361:
complexes, have a lower charge and
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ange 326-400 cm -1 (weak) for Pt-Cl
Page 364 and 365:
ButPt, HexPt, OctPt and DecPt, were
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7.3 Results 7.3.1 DFT Calculations
Page 368 and 369:
Structure HOMO LUMO EnPt (C2h) Prop
Page 370 and 371:
Absorbance Table 7.2: Summary of pK
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coordination to the soft Pt(II) cen
Page 374 and 375:
observed at -2962.4 and -3024.1 ppm
Page 376 and 377:
H 3N NH 3 Pt NH 2 OH 2 n NH 3 NH 2
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k obs2 , in s -1 -3 TU 1.2x10 DMTU
Page 380 and 381:
7.3.4 Activation Parameters The tem
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density is located on the metal cen
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acetylmethionine, which reported th
Page 386 and 387:
References 1 (a) B. Rosenberg, L. V
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32 N. Summa, J. Maigut, R. Puchta a
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Appendix 7 Table S7.1: Summary of s
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k obs(2 nd ) , in s -1 0.00020 0.00
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ln(k 2(2 nd ) /T) -8.5 -9.0 -9.5 -1
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k obs(1 st ) , in s -1 0.06 TU DMTU
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ln(k 2(1 st ) /T) -3.2 TU DMTU TMTU
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Table S7.11: Summary of kobs(2 nd )
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%T 22.0 20 18 16 14 12 10 8 6 4 2 0
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k st obs(1 ) , in s-1 0.10 0.08 0.0
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ln(k st 2(1 ) /T) -4.0 TU DMTU TMTU
Page 410 and 411:
Figure S7.23: Mass spectra for HexP
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Table S21: Average observed rate co
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Table S7.23: Summary of kobs(2 nd )
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90.0 80 70 60 50 40 30 20 %T 10 0 -
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Figure S7.37: Mass spectrum for Hex
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Chapter 8 Tuning Reactivity of plat
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dinuclear Pt(II) complexes to relea
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finally Pt2. The order of reactivit
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• prolonged survival in the cell
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Tuning Reactivity of Platinum(II) Complexes

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