Synergy of intercalation and coordination binding to design novel DNA-targeting antineoplastic metallodrugs
Roy, Sudeshna
Citation
Roy, S. (2008, November 25). Synergy of intercalation and coordination binding to design novel DNA-targeting antineoplastic metallodrugs. Retrieved from
https://hdl.handle.net/1887/13281
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License: Licence agreement concerning inclusion of doctoral thesis in the Institutional Repository of the University of Leiden
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Synergy of intercalation and coordination binding to design novel DNA-targeting antineoplastic metallodrugs
PROEFSCHRIFT
ter verkrijging van
de graad van Doctor aan de Universiteit Leiden,
op gezag van Rector Magnificus Prof. Mr. Paul F. van der Heijden, volgens besluit van het College voor Promoties
te verdedigen op dinsdag 25 November, 2008 klokke 11.15 uur
door
Sudeshna Roy
geboren te Midnapore, India in 1976
Promotiecommisie
Promotor : Prof. Dr. J. Reedijk
Referent : Prof. Dr. E. Alessio (Università di Trieste)
Overige leden : Prof. Dr. J. Brouwer Dr. J. G. Haasnoot Dr. D. de Vos
Dr. G. P. van Wezel
Cover-page illustration
According to Indian philosophy, the symbol of knowledge is white swan. This resembles the journey from darkness of ignorance to eternal sunshine of knowledge. The back cover
symbolises the application of green energy for day-to-day life.
Printed by: CPI Wöhrmann Print Service, Zutphen.
To the pyramid of my life…
Maa-Baabi Bhai Bubu Dushtu
The opposite of a correct statement is a false statement. But the opposite of a profound truth may well be another profound truth.
Niels Bohr (1885-1962)
Contents
Abbreviations
Ligands and compounds
Chapter 1 Introduction 1
Chapter 2 Derivatised phenanthrolines and two platinum(II) compounds as DNA-targeting anticancer or
antimicrobial drugs 75
Chapter 3 Synthesis, cytotoxicity assay and model-base studies of derivatised pyridine and pyrimidine
compounds of platinum(II) 103
Chapter 4 DNA and protein interaction of derivatised
pyridine and pyrimidine compounds of platinum(II) 131 Chapter 5 Comparative studies of DNA cleavage,
conformational change and antiproliferative activity of platinum(II) and copper(II)
compounds of Hpyramol 159
Chapter 6 Synthesis, crystal structure and biological studies of a mononuclear ruthenium(II)-
Hpyrimol compound 187
Chapter 7 Mono- and dinuclear ruthenium compounds
coordinated to terpyridine as a carrier ligand 207 Chapter 8 Dinuclear compounds with a flexible linker
and comparison of their DNA interaction modes 229 Chapter 9 Summary, general discussion and perspective 249
Samenvatting Résumé Publications Acknowledgement
ii
2-clip-phen N-[2-[(1,10-phenanthrolin-2-yl-NN1,NN10)oxy]-1-[[(1,10-phenanthrolin-2-yl- NN1,NN10)oxy]methyl]ethyl]acetamide
9-EtG 9-Ethylguanine
A2780 Cisplatin sensitive ovarian carcinoma cell line A2780R Cisplatin resistant ovarian carcinoma cell line A498 Renal cancer cell line
AA Ascorbic Acid
APL Acute Promyelocytic Leukaemia ATP Adenosine TriPhosphate BSA Bovine Serum Albumin bp base pair bpy 2,2'-Bipyridine
cbdca 1,1-cyclobutanedicarboxylic acid CD Circular Dichroism
Cisplatin Cis-diamminedichloridoplatinum(II) CML Chronic Myelogenous Leukaemia COSY COrrelation SpectroscopY CT DNA Calf Thymus DNA
dipea N-ethyldiisopropylamine dipm 2,2'-Dipyrimidinylamine
dmf N,N-Dimethylformamide dmso Dimethyl sulfoxide DNA DeoxyriboNucleic Acid
dop 5,6-Dioxime-1,10-phenanthroline dpa 2,2'-Dipyridylamine dppz Dipyrido[3,2-a:2,3-c]phenazine
dpq Dipyrido[3,2-f:2´,3´-h]quinoxaline dtdeg Bis-[4'-(2,2:6',2"-terpyridyl)]-diethyleneglycol ether EA Elemental Analysis
ESI-MS ElectroSpray Ionization-Mass Spectroscopy EtBr Ethidium Bromide
EVSA-T Breast cancer cell line (estrogen and progesterone receptor negative) FAAS Flameless Atomic Absorption Spectroscopy
H226 Non-small cell lung cancer cell line hat 1,4,5,8,9,12-hexaazatriphenylene
Hpyramol 4-Methyl-2-N-(2-pyridylmethyl)aminophenol
Abbreviation
iii
Hpyrimol 4-Methyl-2-N-(2-pyridylmethylene)aminophenol
IC50 Concentration of a compound that induces 50% growth inhibition in cells compared to untreated cells given in M
ICD Induced Circular Dichroism IGROV Ovarian cancer cell line
L1210(0) Cisplatin sensitive murine leukemia cell line L1210(2) Cisplatin resistant murine leukemia cell line M Molar concentration
m/z Ratio of mass upon charge M19 MEL Melanoma cell line
MCF7 Breast cancer cell line (estrogen and progesterone receptor positive) MIC Minimum Inhibitory Concentration
MTT 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide NMR Nuclear Magnetic Resonance Spectroscopy
NP Nucleotide Phosphate nt nucleotide
P Partition coefficient PBS Phosphate Buffered Saline phen 1,10-Phenanthroline
phendione 1,10-Phenanthroline-5,6-dione ppm Parts Per Million
SAR Structure Activity Relationship SRB SulfoRhodamine B
tatpp 9,11,20,22-tetra-aza-tetrapyrido[3,2-a:2'3'-c:3'',2''-l:2''',3''']-pentacene TEMPO 2,2,6,6-TEtraMethylPiperidine-1-Oxyl
terpy 2,2:6',2"-Terpyridine tpm tris(1-pyrazolyl)methane UV-vis UltraViolet-VISible WIDR Colon cancer cell line
iv
Ligands and compounds
O
N N O
L1
N N N
N
L2
N N N
N
L3
N N HON
HON
L4
N N
L5
N N NH
L6 N
N
N N NH
L7
N CH3
OH N H
L8
N CH3
N OH
L9
N
N N
L10
N
N N
Cl
L11 N
N N
O
O O
N N N
L12
v
N O
O
Pt N
Cl Cl
C1
N N
N Pt
N
Cl Cl
C2
N N NH
Pt Cl Cl
C3
N N
NH
Pt NH3 NH3
(NO3)2
C4
N N
N N NH
Cl Pt Cl
C5
N CH3
N
O Pt
C7Cl
N N
N N NH
Pt NH3 NH3
(NO3)2
C6
N CH3
N O Cu
Cl
C8
N
CH3 N
OH N CH3
N OH
M Cl Cl
C9
vi Cl
N
N N
Ru Cl Cl
C10
Cl N
N N
Ru Cl Cl Cl
C11
N
N OH N
N N
Ru Cl
C12
N N N
O O O
N N N N
N
N N
Ru Ru N
N
N N Cl Cl
Cl2
C13
N N N
O O O
N N N
N
N Ru Ru N
N Cl Cl
Cl2
C14
vii
N N N
O
O O
N N
Ru N Ru
Cl Cl
Cl Cl Cl
Cl
C15
N N N
O
O O
N N
Pt N Pt Cl
Cl Cl2
C16
N N N
O
O O
N N
Cu N Cu
Cl Cl
Cl
Cl
C17
