Chapter 1 General Introduction 11
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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 Version: Corrected Publisher’s Version Licence agreement concerning inclusion of doctoral thesis in the License: Institutional Repository of the University of Leiden Downloaded from: https://hdl.handle.net/1887/12619 Note: To cite this publication please use the final published version (if applicable). 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 6 List of complexes used in this thesis 8 Chapter 1 General introduction 11 Chapter 2 Influence of the copper coordination geometry on the 47 DNA cleavage activity of Clip-Phen complexes studied by DFT. Chapter 3 A New Approach for the Preparation of Efficient 63 DNA Cleaving Agents: Ditopic Copper-Platinum Complexes Based on 3-Clip-Phen and Cisplatin. Chapter 4 DNA Cleavage and binding selectivity of a 81 heterodinuclear Pt-Cu(3-Clip-Phen) complex. Chapter 5 Platinated copper(3-Clip-Phen) complexes as effective 103 DNA-cleaving and cytotoxic agents. Chapter 6 Change of the bridge linking a platinum moiety and 117 the DNA-cleaving agent Cu(3-Clip-Phen). Chapter 7 Triazine as a building block for the generation of 131 multifunctional heteronuclear platinum/copper complexes. Chapter 8 Exploring the DNA-cleaving abilities of novel 147 heteronuclear ruthenium-copper complexes. Chapter 9 Summary, general discussions and perspectives 165 Samenvatting 172 Curriculum Vitae 175 List of publications 176 Acknowledgements 178 _|áà Éy tuuÜxä|tà|ÉÇá 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 _|áà Éy vÉÅÑÄxåxá âáxw |Ç à{|á à{xá|á DFT calculated complexes O O N N N N N N Cu+,2+ Cu+,2+ Cu+,2+ N N N N N N O O dft 1dft 2dft 3 O O O O N N N N N N +,2+ +,2+ +,2+ Cu NH2 Cu N Cu N N N N H N N O O O 4dft 5dft 6dft O N N Cu+,2+ N N O 7dft Chapter 2 The complexes have been prepared by Pitié et al. Eur. J. Inorg. Chem. 2003, 528 The prepared Complexes O O N N N N NH NH2 NH NH2 N Pt CuCl2 N Pt N N H Cl Cl N N H Cl Cl O 3CP-6-Pt O Cu3CP-6-Pt O O N N N N HN NH2 HN NH2 N Pt CuCl2 N Pt N N H Cl Cl N N H Cl Cl O 3CP-10-Pt O Cu3CP-10-Pt Chapter 3 O O N N N N NH NH2 CuCl2 NH NH2 N N Pt N N Pt O Cl Cl O Cl Cl 3CP-0-Pt Cu3CP-0-Pt Chapter 4 8 N N l N C 2 N N N u C O N O N H N H N 2 O 2 O H3N H3N Pt asym-cis Pt Cu(asym-cis) Cl Cl Cl Cl N N l 2 N uC N N N C O N O N H2N H2N O Cl O Cl Pt asym-trans Pt Cu(asym-trans) H N Cl H3N Cl 3 N N l 2 N N uC N N C O N O N H2N H2N O Cl O Cl Pt sym-trans Pt Cu(sym-trans) Cl Cl O H2N O H2N N O N O l 2 N N uC N N C N N Chapter 5 O O N N H N N H N N N HN NH2 CuCl2 N HN NH2 H H N N 3CP-6-NH-6-Pt Pt N N Cu3CP-6-NH-6-Pt Pt O Cl Cl O Cl Cl O N N H N N HN NH2 H Pt N N 3CP-6-NH-10-Pt O Cl Cl O N N H N CuCl2 N HN NH2 H Pt N N Cu3CP-6-NH-10-Pt O Cl Cl Chapter 6 9 Cl Cl N N N N O N N NH O N N NH HN 2 NH HN 2 NH H Pt 3 H Pt 3 Cl Cl Cl Cl N O 3CP-triz-Pt N O Cu3CP-triz-Pt l N N N C 2 N Cu N N + HN NH2 NH HN NH2 NH Pt 3 Pt 3 N N Cl Cl N N Cl Cl O N N NH O N N NH HN 2 NH HN 2 NH H Pt 3 H Pt 3 Cl Cl Cl Cl N O 3CP-triz-2Pt N O Cu3CP-triz-2Pt l 2 N N N uC N C N N N N N N N N O N N NH O N N NH HN 2 NH HN 2 NH H Pt 3 H Pt 3 Cl Cl Cl Cl N O 3CP-triz-F-Pt N O Cu3CP-triz-F-Pt l 2 N N N uC N C N N Chapter 7 N N N N Cl Cl N Cu Cu(terpy) N Ru N O O O N Cu Cl Cl N N N [Ru(dtdeg)Cu] N N N N N Cl Cl Cu N O O O N Ru N O O O N Cu Cl Cl N N N N [Cu2(dtdeg)2Ru] N N N N N N Cl Cl Cu N O O O N Ru N O O O N Ru N O O O N Cu Cl Cl N N N N N N [Cu2(dtdeg)3Ru2] N N N Cl N N Cl Cl N Ru N O O O N Cu Cl Ru N O O O N Cu Cl Cl Cl N N Cl N N [Cu(dtdeg)Ru(bipy)Cl] [Cu(dtdeg)RuCl3] Chapter 8 10 V{tÑàxÜ D General introduction Chapter 1 1.1 Fighting cancer Cancer is a leading cause of death worldwide. In 2005 it accounted for approximately 13% of all deaths.[1] Cancer is a generic term for a group of over 100 diseases that exhibit some common characteristics, namely the uncontrolled growth of cells, and which can affect and damage adjacent normal tissues.[2] It may also spread through the body and reach other organs, a process referred to as metastasis. Lung, breast, colorectal and prostate cancers are the most frequently occurring and cause the majority of deaths. Abnormalities in genes responsible for cell growth and repair can cause cancer. The changes in the genes are often the result of the influence of external agents, such as tobacco smoke, radiation, chemicals or infections by viruses like for example Hepatitis B.