Tuning Reactivity of Platinum(II) Complexes

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Table of Contents-1 Chapter 1 .................................................................................................................................................................. 1 1.0 Introduction ...................................................................................................................................................... 1 1.1 Cancer disease ............................................................................................................................................. 1 1.2 Cancer Treatment ...................................................................................................................................... 1 1.2.1 Chemotherapy ......................................................................................................................................... 2 1.3 Platinum chemistry .................................................................................................................................. 2 1.3.1 Platinum-Based Anticancer Drugs ................................................................................................ 3 1.3.2 Cisplatin ...................................................................................................................................................... 4 1.3.2.1 Mechanism of Action ........................................................................................................................ 4 1.3.2.2 Cellular Uptake .................................................................................................................................... 5 1.3.2.3 Hydrolysis .............................................................................................................................................. 5 1.3.2.4 DNA adducts and Cell Response ................................................................................................. 6 1.3.2.5 Cisplatin Resistance .......................................................................................................................... 8 1.3.2.6 Competition between N– and S–Donor Nucleophiles ...................................................... 8 1.3.3 New and “Non-classical” platinum complexes ..................................................................... 10 1.3.3.1 Second generation Cisplatin Analogues ............................................................................... 10 1.3.3.2 Platinum(IV) complexes .............................................................................................................. 12 1.3.4 Terpyridine platinum(II) complexes ......................................................................................... 13 1.3.5. Multinuclear Platinum(II) complexes ...................................................................................... 14 1.3.5.1 Amino Linkers .................................................................................................................................. 15 1.3.5.2 Aromatic linkers .............................................................................................................................. 16 1.4 Kinetic Interest ........................................................................................................................................ 17 1.5 Aim and Scope of this Study .............................................................................................................. 17 References .............................................................................................................................................................. 20 List of Figures Figure 1.1: Classification of chemotherapy drugs................................................................................ 2 Figure 1.2: Chemical structures of selected platinum compounds ........................................................ 4 Figure 1.3: Intracellular hydrolysis and bio-activation of cisplatin in aqueous solution leading to binding at DNA in the cell nucleus. ........................................................................................................ 6 i
Figure 1.4: DNA-adduct formation with cisplatin leaving two amino groups coordinated on the platinum atom. The main adducts formed in the interaction cisplatin with DNA: (a) interstrand crosslink; (b) 1,2-intrastrand cross-link; (c) 1,3-intrastrand cross-link and; (d) protein-DNA cross-link. ..... 7 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. ............... 9 Figure 1.6: DNA adducts formed by oxaliplatin 13 . ............................................................................... 11 Figure 1.7: Structure of a sterically hindered platinum(II) complex (ZD0473) that circumvents cisplatin resistance. ............................................................................................................................. 12 Figure 1.8: Selected Pt(II) metallo-intercalators: terpy = terpyridine, phen = phenanthroline, 4picoline = 4-methylpyridine, en = 1,2-diaminoethane, and HET = 2-hydroxyethanethiolato ligand. ................................................................................................................................................... 13 Figure 1.9: Selected Multinuclear platinum(II) complexes with flexible amino- and rigid azine and azoles ligands. , .............................................................................................................................. 15 Figure 1.10: Structure of extended terpy Pt(II) complexes; blue ring for isoquinoline ring and red for phenanthroline ring system. .................................................................................................. 18 ii
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 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 40 and 41: transformational pathways that comp
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
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c. Oxidizability: Ligands that are
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Table 2.1: A selection of n o pt va
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eaction with different nucleophiles
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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
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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
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Page 204 and 205:
Page 206 and 207:
k obs(1 st ) , s -1 0.06 0.04 0.02
Page 208 and 209:
Page 210 and 211:
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
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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
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pzn PPM -1750.0 -1850.0 -1950.0 -20
Page 264 and 265:
Page 266 and 267:
Figure S5.13: UV/Visible spectra fo
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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
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SpinWorks 2.5: znPt(II)-OP4 in D2O
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Figure S5.31: Mass spectrum for com
Page 288 and 289:
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
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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
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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
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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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-2304.16 ppm H 3N PPM -2200.0 -2220
Page 348 and 349:
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
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complexes, have a lower charge and
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ange 326-400 cm -1 (weak) for Pt-Cl
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ButPt, HexPt, OctPt and DecPt, were
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7.3 Results 7.3.1 DFT Calculations
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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
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observed at -2962.4 and -3024.1 ppm
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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
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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
Page 426 and 427:
finally Pt2. The order of reactivit
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• prolonged survival in the cell
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