The design and synthesis of novel heterodinuclear complexes combining a DNA-cleaving agent and a DNA-targeting moiety
Hoog, P. de
Citation
Hoog, P. de. (2008, February 28). The design and synthesis of novel heterodinuclear complexes combining a DNA-cleaving agent and a DNA-targeting moiety. Retrieved from https://hdl.handle.net/1887/12619
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The design and synthesis of novel heterodinuclear complexes combining a
DNA-cleaving agent and a DNA-targeting moiety
The search for novel anticancer agents
Proefschrift
ter verkrijging van de graad van Doctor aan de Universiteit Leiden, op gezag van de Rector Magnificus prof. mr. P.F. van der Heijden, volgens besluit van het College
voor Promoties te verdedigen op donderdag 28 februari 2008 klokke 16.15 uur
door Paul de Hoog
geboren te Sliedrecht, Nederland in 1979
Samenstelling promotiecommissie
Promotor: Prof. Dr. Jan Reedijk Co-promotor: Dr. Patrick Gamez
Referent: Prof. Dr. G.A. van der Marel
Overige Leden: Prof. Dr. B. Meunier (Palumed, Toulouse) Dr. M. Pitié (LCC, Toulouse)
Prof. Dr. J. Brouwer
This work was possible thanks to the financial support of the Chemical Research Council of the Netherlands through the CERC3 program.
What gets us into trouble is not what we do not know, it is what we know for sure that just is not so.
Mark Twain (1835-1910)
Aan mijn ouders, Debbie en Jesse
VÉÇàxÇàá
List of abbreviations
List of complexes used in this thesis
Chapter 1 General introduction
Chapter 2 Influence of the copper coordination geometry on the DNA cleavage activity of Clip-Phen complexes studied by DFT.
Chapter 3 A New Approach for the Preparation of Efficient DNA Cleaving Agents: Ditopic Copper-Platinum Complexes Based on 3-Clip-Phen and Cisplatin.
Chapter 4 DNA Cleavage and binding selectivity of a heterodinuclear Pt-Cu(3-Clip-Phen) complex.
Chapter 5 Platinated copper(3-Clip-Phen) complexes as effective DNA-cleaving and cytotoxic agents.
Chapter 6 Change of the bridge linking a platinum moiety and the DNA-cleaving agent Cu(3-Clip-Phen).
Chapter 7 Triazine as a building block for the generation of multifunctional heteronuclear platinum/copper complexes.
Chapter 8 Exploring the DNA-cleaving abilities of novel heteronuclear ruthenium-copper complexes.
Chapter 9 Summary, general discussions and perspectives Samenvatting
Curriculum Vitae List of publications Acknowledgements
6 8 11 47
63
81
103
117
131
147
165 172 175 176 178
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5-MF 5-methylfuranone A Adenine Å Ångstrom A498 Renal cancer cell line A549 Lung cancer cell line ATP Adenosine TriPhosphate B Becke
Bipy Bipyridine
Boc tert-butyl acetate Boc2O Di-tert-butyl dicarbonate C Cytosine
COSY Correlation Spectroscopy CTP Cytidine TriPhosphate DCM DiChloroMethane
DFT Density Functional Theory DIPEA DiIsoPropylEthylAmine DMF DimMethylFormamide DMSO DiMethyl SulfOxide DNA DeoxyriboNucleic Acid
DPPZ DiPyrido[3,2-a:2¢,3¢-c]PhenaZine DSB Double-Strand Breaks
EDTA EthyleneDiamine Tetraacetic Acid EPR Enhanced Permeability and Retention ESI Electrospray Ionization
EVSA-T Breast cancer cell line FCS Fetal Calf Serum
Fmoc (9H-fluoren-9-yl)methylcarbamate
Fmoc-Osu N-(9-Fluorenylmethoxycarbonyloxy)succinimide G Guanine
GC Gas Chromatography GSH Glutathione
GTP Guanosine TriPhosphate
H226 Non-small cell lung cancer cell line HCT-15 Colorectal cancer cell line
HeLa Cervical cancer cell line
HEPES 4-(2-HydroxyEthyl)-1-PiperazineEthaneSulfonic acid HMG High-Mobility Group
HPLC High Performance Liquid Chromatography Hs683 Glioblastomas cell line
IGROV Ovarian cancer cell line LoVo Colorectal cancer cell line M19 MEL Melanoma cell line MCF7 Breast cancer cell line MEM Minimal Essential Medium MeOH Methanol
MPA MercaptoPropionic Acid
6
MS Mass Spectroscopy
MTT 3-(4,5-dimethylthiazol)-2-yl)-2,5-diphenyl-2H-tetrazolium bromide NER Nucleotide Excision Repair
NMR Nuclear Magnetic Resonance OD Optical Density
ODN Oligonucleotide P Perdew
PAGE PolyAcrylamide Gel Electrophoresis PBS Phosphate Buffered Saline
PCC Pyridinium ChloridotrioxidoChromate Phen Phenanthroline
Py 2-Pyridyl
QZ4P Quadruple ζ with four polarization functions RNA RiboNucleic Acid
RPMI Roswell Park Memorial Institute medium RT Room Temperature
SPE Single-Point Energies SRB SulfoRhodamine B SSB Single-Strand Breaks STO Slater Type Orbital T Thymine
Taq Thermus Aquaticus TBE Tris-Borate-Edta Terpy Terpyridine
TFA TriFluoroAcetic acid THF TetraHydroFuran TMS TetraMethylSilane
Tris 2-Amino-2-(hydroxymethyl)propane-1,3-diol TTP Thymidine TriPhosphate
TZ2P Triple ζ with two polarization functions U2-OS human osteosarcoma cell line
U-373MG Glioblastomas cell line UV UltraViolet
Vis Visible
WIDR Colon cancer cell line
ZORA Zeroth-Order Regular Approximation
7
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DFT calculated complexes
N N
O NH2 O N N
Cu+,2+
N N
O
O N N
Cu+,2+
N N
O NH O N N
Cu+,2+
O
N N
O
O N N
Cu+,2+
N N
N N
Cu+,2+
N N
O
O N N
Cu+,2+
N N
O
O N N
Cu+,2+
1dft 2dft 3dft
4dft 5dft 6dft
7dft
Chapter 2 The complexes have been prepared by Pitié et al. Eur. J. Inorg. Chem. 2003, 528
The prepared Complexes
N N
O NH O N N
NH NH2
3CP-6-Pt Pt Cl Cl
N N
O NH O N N
NH NH2
Cu3CP-6-Pt Pt Cl Cl CuCl2
N N
O NH O N N
HN NH2
3CP-10-Pt
Pt Cl Cl
N N
O NH O N N
HN NH2
Cu3CP-10-Pt
Pt Cl Cl CuCl2
Chapter 3
N N
O NH O N N
NH2 Pt Cl Cl 3CP-0-Pt
N N
O NH O N N
NH2 Pt Cl Cl Cu3CP-0-Pt CuCl2
Chapter 4
8
Pt H2N
Cl Cl O
O N N
N N
H3N Pt
H2N
Cl Cl O
O N N
N N
H3N
asym-cis Cu(asym-cis)
CuCl2
Pt H2N
H3N Cl O
O N N
N N
Cl Pt
H2N
H3N Cl O
O N N
N N
Cl asym-trans Cu(asym-trans)
CuCl2
Pt H2N
O
O N N
N N
H2N O
N O
N N
N
Cl Pt Cl
H2N O
O N N
N N
H2N O
N O
N N
N
Cl Cl
sym-trans Cu(sym-trans)
CuCl2
CuCl2
Chapter 5
N N
O N H O N N
HN
HN NH2 Pt Cl Cl 3CP-6-NH-6-Pt
N N
O N H O N N
HN
HN NH2 Pt Cl Cl Cu3CP-6-NH-6-Pt
CuCl2
N N
O NH O N N
HN
HN NH2 Pt Cl Cl 3CP-6-NH-10-Pt
N N
O NH O N N
H
N HN NH2
Pt Cl Cl Cu3CP-6-NH-10-Pt
CuCl2
Chapter 6
9
N N
N
N N
O HN
O N N
N
H NH2
PtCl Cl
NH3
3CP-triz-Pt Cl
N N
N
N N
O HN
O N N
N
H NH2
PtCl Cl
NH3
Cu3CP-triz-Pt Cl
CuCl2
N N
N
N N
O HN
O N N
N
H NH2
PtCl Cl
NH3 3CP-triz-2Pt
HN NH2
Cl Pt NH3
Cl N
N N
N N
O HN
O N N
N
H NH2
PtCl Cl
NH3 Cu3CP-triz-2Pt
HN NH2
Cl Pt NH3 Cl
+
CuCl2
CuCl2
N N
N N
N N
O HN
O N N
N
H NH2
PtCl Cl
NH3 3CP-triz-F-Pt
N N
N N
N N
O HN
O N N
N
H NH2
PtCl Cl
NH3 Cu3CP-triz-F-Pt
Chapter 7
N N
N N
N N
Ru O O O N
N
N Cu N
N N
Cl Cl Cu
Cl Cl
Cu(terpy)
[Ru(dtdeg)Cu]
O O O N N N
Cu N
N
N N
N N
Ru O O O N
N
N Cu
Cl Cl Cl
Cl
[Cu2(dtdeg)2Ru]
O O O N N N
Cu N
N
N N
N N
Ru O O O N
N
N N
N N
Ru O O O N
N
N Cu
Cl Cl Cl
Cl
[Cu2(dtdeg)3Ru2]
N N
Cl N
N N
Ru O O O N
N
N Cu Cl
Cl
Cl N
N N
Ru O O O N
N
N Cu Cl
Cl
Cl Cl
[Cu(dtdeg)Ru(bipy)Cl] [Cu(dtdeg)RuCl3]
Chapter 8
10
