Design and development of polynuclear ruthenium and platinum
polypyridyl complexes in search of new anticancer agents
Schilden, Karlijn van der
Citation
Schilden, K. van der. (2006, January 26). Design and development of polynuclear
ruthenium and platinum polypyridyl complexes in search of new anticancer agents.
Retrieved from https://hdl.handle.net/1887/4377
Version: Corrected Publisher’s Version
License: Licence agreement concerning inclusion of doctoral thesis in theInstitutional Repository of the University of Leiden Downloaded from: https://hdl.handle.net/1887/4377
Design and Development of
Polynuclear Ruthenium and Platinum
Polypyridyl Complexes
in Search of New Anticancer Agents
PROEFSCHRIFT
ter verkrij
ging van
de graad van Doctor aan de Universiteit Leiden,
op gezag van Rector M agnificus Dr.
D.
D.
Breimer,
hoogleraar in de faculteit der W iskunde
en Natuurwetenschappen en die der Geneeskunde,
volgens besluit van het College voor Promoties
te verdedigen op donderdag 26 j
anuari 2006
klokke 15.
15 uur
door
Promotiecommissie
Promotor : Prof. Dr. J. Reedijk
Co-promotor : Dr. J. G. Haasnoot
Referent : Prof. Dr. E. Alessio (Università di Trieste)
Overige leden : Prof. Dr. J. Brouwer Prof. Dr. H. S. Overkleeft
Prof. Dr. G. Sava (Università di Trieste) Dr. M . Ubbink
The research described in this thesis was financially supported by the Council for Chemical Sciences of the Netherlands Organization for Scientific Research (CW -NW O). Financial support of COST Chemistry D20 for the stay in Brno is gratefully acknowledged.
Cover: Picture of the crystal structure of the dinuclear complex [(tpy)Ru(dtdeg)PtCl]3+ and microscopic image of cisplatin-sensitive human ovarian carcinoma cells after three days of incubation with 20 µM of the tetranuclear complex [Cl3Ru(dtdeg)Ru(dtdeg)Ru(dtdeg)RuCl3]Cl4.
Table of contents
List of abbreviations 6
Chapter 1 9
General introduction
Chapter 2 47
A paramagnetic dinuclear ruthenium(II)-ruthenium(III) complex: synthesis and strategy for 1H NM R studies
Chapter 3 65
Dinuclear ruthenium(II) complexes with long and flexible linkers: rotational behavior of coordinated 9-ethylguanine and biological properties
Chapter 4 87
Heterodinuclear ruthenium-platinum complexes with long and flexible linkers: crystal structure and cytotoxicity
Chapter 5 109
Trinuclear and tetranuclear ruthenium and platinum complexes with long and flexible linkers: syntheses, characterization and biological properties
Chapter 6 133
Chapter 7 151 Summary, general discussion and future prospects
Samenvatting 159
Ontwerp en ontwikkeling van polynucleaire rutheniumcomplexen en ruthenium-platinacomplexen
Op zoek naar nieuwe medicijnen tegen kanker
Curriculum vitae 163
List of Publications 164
6
List of abbreviations
A2780cis cisplatin-sensitive human ovarian carcinoma cellline A2780R cisplatin-resistanthuman ovarian carcinoma cellline A549 lung cancer cellline
bpy 2,2’-bipyridine cod cyclooctadiene
COSY Correlation Spectroscopy
d doublet
DM F dimethylformamide DM SO dimethylsulfoxide DNA deoxyribonucleic acid
dtdeg bis[4’-(2,2’:6’,2”-terpyridyl)]-diethyleneglycolether H4edta ethylene diamine tetraacetic acid
en ethylene diamine
EPR electron paramagnetic resonance spectroscopy ESI-M S electrospray ionization mass spectroscopy EtOH ethanol
9egua 9-ethylguanine
FAAS flameless atomic absorption spectroscopy FBS fetalbovine serum
GSH glutathione
HBL-100 non tumorigenic epithelialcellline HCT-15 colorectalcancer cellline
hr hour
Hs683 glioblastoma cellline
IC50 concentration of a compound thatinduces 50 % of growth inhibition of
cells compared to untreated cells J couplin constantin NM R
7
L1210/0 cisplatin-sensitive mouse leukemia cell line L1210/2 cisplatin-resistant mouse leukemia cell line LoVo colorectal cancer cell line
M molar
MCF-7 breast cancer cell line MeOH methanol
MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide m/z mass to charge ratio
NMR nuclear magnetic resonance NOE nuclear Overhauser effect
NOESY nuclear Overhauser effect spectroscopy OD optical density
PBS phosphate buffered saline ppm parts per million
q quartet
qpy 4’-pyridyl-2,2’:6’,2”-terpyridine RT room temperature
s singlet, or second
SAR structure-activity relationships
t triplet
T1 nuclear longitudinal relaxation time
T2 nuclear transverse relaxation time
