Dimeric ligands for G-protein coupled receptors that are involved in human reproduction, namely the gonadotropin releasing hormone receptor, the luteinizing hormone receptor and the follicle... Show moreDimeric ligands for G-protein coupled receptors that are involved in human reproduction, namely the gonadotropin releasing hormone receptor, the luteinizing hormone receptor and the follicle-stimulating hormone receptor, were synthesized and biologically evaluated. Show less
In this thesis a combined approach is described to investigate the constitutive activity of G protein protein-coupled receptors (GPCRs) using human adenosine A2B receptors and to evaluate disease... Show moreIn this thesis a combined approach is described to investigate the constitutive activity of G protein protein-coupled receptors (GPCRs) using human adenosine A2B receptors and to evaluate disease-related constitutive GPCR activity as a target for treatment. To this end a yeast expression system together with pharmacological and theoretical receptor models have been applied. In Chapter 2 the advantages of yeasts as tools to study GPCRs are reviewed. Adapted yeast cells able to communicate with mammalian GPCRs have become available and provide a very convenient system to express mutated receptors. A major advantage of yeast cells over mammalian cells extends from easy culturing conditions to the characteristic of yeast cells to allow entry of only a single plasmid. This latter property in combination with the robust screening assay based on yeast growth makes them an ideal test system to study randomly as well as site-directed mutated receptors. In chapters 3 to 5 this yeast growth assay is the main experimental tool to evaluate the functional properties of random and site-directed mutant receptors. In chapters 3 and 4 the yeast system is exploited to study inverse agonism of the human adenosine A2B receptor. At first, constitutively active mutant (CAM) human adenosine A2B receptors have been used to discriminate inverse agonists of the adenosine A2B receptor from A2B receptor antagonists. As a result, three inverse agonists ZM241385, DPCPX and MRS1706 were identified and their rank order of efficacy determined. Moreover, an interesting system-dependent phenomenon was noticed, that is the intrinsic activities of the inverse agonists were affected by the level of constitutive activity. It was demonstrated that inverse agonists show the greatest intrinsic activity on receptors displaying a medium level of constitutive activity. To further investigate the relationship between the effectiveness of an inverse agonist and the level of constitutive activity of the receptor, the two-state receptor model was introduced in both Chapter 3 and Chapter 4. According to this two-state model, both the receptor isomerization constant (L) and the intrinsic efficacy (_) of the inverse agonist determines the sensitivity to detect the intrinsic activity of an inverse agonist which is reflected by the observed experimental window. The biggest experimental window can be achieved on receptors with an L value equaling the reciprocal square root of _. Our experiments show that mutant A2B receptors with an intermediate level of constitutive activity possess the greatest experimental window, whereas mutants with a low level of constitutive activity showed small experimental windows and highly constitutively active mutants did not respond to our tested inverse agonists. Based on these findings we conclude that receptors with intermediate levels of constitutive activity should be the most sensitive screening tools for detecting inverse agonists. In Chapter 5 the activation of the human adenosine A2B receptor was investigated. To investigate the role of the NxxxNPxxY motif and the potential salt bridge between TM1 (E14) and TM7 (H280) in receptor activation, site-directed mutagenesis was applied to yield 15 mutant A2B receptors. The mutations were selected based on an adenosine A2B receptor model using the structure of bovine rhodopsin as a template. The expression levels of these mutants were determined by western blot analysis and the activation of the receptors was measured in the presence or absence of the following agonists NECA, CPA, CGS21680, IBMECA and LUF5833. None of the mutant receptors displayed constitutive activity. On the contrary, most mutants had a reduced potency and/or efficacy, e.g. mutants N282Q, N282R, N286A, N286Q, N286R, and Y290F showed impaired activation and mutants Y290N, E14H, H280E, E14H/H280E, I61A, I61D and I61K could not be activated by any of the agonists tested. Among all the mutants constructed, only N282R and N286R receptors behaved similarly to the wild-type receptor. Moreover, mutant N286A reduced receptor expression and H280E and E14H/H280E abolished receptor expression. These results suggest an important role for the NxxxNPxxY motif and the potential salt bridge in receptor expression and activation. The recent publication of the _2-adrenergic receptor structure enabled us to construct a second model of the adenosine A2B receptor. Comparison of the two A2B receptor models based on these two different templates is also described in Chapter 5. The various effects caused by mutations in the NxxxNPxxY motif and the potential salt bridge of different receptors in both our experiments and from literature do suggest that receptor activation is a receptor-specific phenomenon. In Chapter 6 we provide a theoretical investigation of the treatment of disease-related constitutively active receptor mutations. Comparison of the characteristics of allosteric ligands with traditional orthosteric ligands using a two-state allosteric model predicts that allosteric ligands display a more complicated interaction with a receptor/endogenous ligand pair and are able to cooperatively modify receptor binding and function. As a result allosteric modulators may affect the level of constitutive activity without changing the potency of the endogenous ligand. Thus allosteric modulators may provide advantages over orthosteric ligands in the treatment of diseases caused by constitutively active GPCR mutations. Finally in Chapter 7, general conclusions about the research described in this thesis are drawn. This is also supplemented by an outlook on some potential aspects of research to be pursued, based upon the application of receptor models, pharmacology models and functional receptor assays. Show less
Each protein is characterized by its unique sequential order of amino acids, the so-called protein sequence. Biology__s paradigm is that this order of amino acids determines the protein__s... Show moreEach protein is characterized by its unique sequential order of amino acids, the so-called protein sequence. Biology__s paradigm is that this order of amino acids determines the protein__s architecture and function. In this thesis, we introduce novel algorithms to analyze protein sequences. Chapter 1 begins with the introduction of amino acids, proteins and protein families. Then fundamental techniques from computer science related to the thesis are briefly described. Making a multiple sequence alignment (MSA) and constructing a phylogenetic tree are traditional means of sequence analysis. Information entropy, feature selection and sequential pattern mining provide alternative ways to analyze protein sequences and they are all from computer science. In Chapter 2, information entropy was used to measure the conservation on a given position of the alignment. From an alignment which is grouped into subfamilies, two types of information entropy values are calculated for each position in the MSA. One is the average entropy for a given position among the subfamilies, the other is the entropy for the same position in the entire multiple sequence alignment. This so-called two-entropies analysis or TEA in short, yields a scatter-plot in which all positions are represented with their two entropy values as x- and y-coordinates. The different locations of the positions (or dots) in the scatter-plot are indicative of various conservation patterns and may suggest different biological functions. The globally conserved positions show up at the lower left corner of the graph, which suggests that these positions may be essential for the folding or for the main functions of the protein superfamily. In contrast the positions neither conserved between subfamilies nor conserved in each individual subfamily appear at the upper right corner. The positions conserved within each subfamily but divergent among subfamilies are in the upper left corner. They may participate in biological functions that divide subfamilies, such as recognition of an endogenous ligand in G protein-coupled receptors. The TEA method requires a definition of protein subfamilies as an input. However such definition is a challenging problem by itself, particularly because this definition is crucial for the following prediction of specificity positions. In Chapter 3, we automated the TEA method described in Chapter 2 by tracing the evolutionary pressure from the root to the branches of the phylogenetic tree. At each level of the tree, a TEA plot is produced to capture the signal of the evolutionary pressure. A consensus TEA-O plot is composed from the whole series of plots to provide a condensed representation. Positions related to functions that evolved early (conserved) or later (specificity) are close to the lower left or upper left corner of the TEA-O plot, respectively. This novel approach allows an unbiased, user-independent, analysis of residue relevance in a protein family. We tested the TEA-O method on a synthetic dataset as well as on __real__ data, i.e., LacI and GPCR datasets. The ROC plots for the real data showed that TEA-O works perfectly well on all datasets and much better than other considered methods such as evolutionary trace, SDPpred and TreeDet. While positions were treated independently from each other in Chapter 2 and 3 in predicting specificity positions, in Chapter 4 multi-RELIEF considers both sequence similarity and distance in 3D structure in the specificity scoring function. The multi-RELIEF method was developed based on RELIEF, a state-of-the-art Machine-Learning technique for feature weighting. It estimates the expected __local__ functional specificity of residues from an alignment divided in multiple classes. Optionally, 3D structure information is exploited by increasing the weight of residues that have high-weight neighbors. Using ROC curves over a large body of experimental reference data, we showed that multi-RELIEF identifies specificity residues for the seven test sets used. In addition, incorporating structural information improved the prediction for specificity of interaction with small molecules. Comparison of multi-RELIEF with four other state-of-the-art algorithms indicates its robustness and best overall performance. In Chapter 2, 3 and 4, we heavily relied on multiple sequence alignment to identify conserved and specificity positions. As mentioned before, the construction of such alignment is not self-evident. Following the principle of sequential pattern mining, in Chapter 5, we proposed a new algorithm that directly identifies frequent biologically meaningful patterns from unaligned sequences. Six algorithms were designed and implemented to mine three different pattern types from either one or two datasets using a pattern growth approach. We compared our approach to PRATT2 and TEIRESIAS in efficiency, completeness and the diversity of pattern types. Compared to PRATT2, our approach is faster, capable of processing large datasets and able to identify the so-called type III patterns. Our approach is comparable to TEIRESIAS in the discovery of the so-called type I patterns but has additional functionality such as mining the so-called type II and type III patterns and finding discriminating patterns between two datasets. From Chapter 2 to 5, we aimed to identify functional residues from either aligned or unaligned protein sequences. In Chapter 6, we introduce an alignment-independent procedure to cluster protein sequences, which may be used to predict protein function. Traditionally phylogeny reconstruction is usually based on multiple sequence alignment. The procedure can be computationally intensive and often requires manual adjustment, which may be particularly difficult for a set of deviating sequences. In cheminformatics, constructing a similarity tree of ligands is usually alignment free. Feature spaces are routine means to convert compounds into binary fingerprints. Then distances among compounds can be obtained and similarity trees are constructed via clustering techniques. We explored building feature spaces for phylogeny reconstruction either using the so-called k-mer method or via sequential pattern mining with additional filtering and combining operations. Satisfying trees were built from both approaches compared with alignment-based methods. We found that when k equals 3, the phylogenetic tree built from the k-mer fingerprints is as good as one of the alignment-based methods, in which PAM and Neighborhood joining are used for computing distance and constructing a tree, respectively (NJ-PAM). As for the sequential pattern mining approach, the quality of the phylogenetic tree is better than one of the alignment-based method (NJ-PAM), if we set the support value to 10% and used maximum patterns only as descriptors. Finally in Chapter 7, general conclusions about the research described in this thesis are drawn. They are supplemented with an outlook on further research lines. We are convinced that the described algorithms can be useful in, e.g., genomic analyses, and provide further ideas for novel algorithms in this respect. Show less
The study described in this thesis was conducted with the aim of developing lipophilic iminosugars as selective inhibitors for glucosylceramide synthase, glucocerbrosidase and _-glucosidase 2 that... Show moreThe study described in this thesis was conducted with the aim of developing lipophilic iminosugars as selective inhibitors for glucosylceramide synthase, glucocerbrosidase and _-glucosidase 2 that are enzymes involved in glucosylceramide metabolism. The study has resulted in many novel inhibitors of these three enzymes among which several that improve upon the inhibition profile of the lead compound in this study. The successful use of lipophilic iminosugars in type 2 diabetes models and the partial elucidation of their mechanism of action therein provide prospects for their development towards therapeutics for diabetes type 2. Show less
This thesis describes an investigation of the potential of electron diffraction for studying three dimensional sub-micro-crystals of proteins and pharmaceuticals. A prerequisite for using electron... Show moreThis thesis describes an investigation of the potential of electron diffraction for studying three dimensional sub-micro-crystals of proteins and pharmaceuticals. A prerequisite for using electron diffraction for structural studies is the predictable availability of tiny crystals. A method for growing such crystals using heterogeneous nucleation is demonstrated. The heterogeneous nucleant (in this case hair fibers) was serendipitously selected. Four different proteins (lysozyme, glucose isomerase, a Fab fragment and potato protease inhibitor) were shown to nucleate preferentially on the selected substrate and sub-micro crystals were grown. Further studies on the mechanism of heterogeneous nucleation using lysozyme as a test protein and different imaging techniques such as atomic force and fluorescent microscopy are also discussed. Sub-micron crystals of potato protease inhibitor and lysozyme were subject of electron diffraction studies. A detailed description of the diffraction experiments is presented. A special focus is given on the sample preparation procedure and in particular the vitrification and the cryo-preservation of the crystals. The preliminary results showed that the heterogeneously grown nano-crystals are well ordered and suitable for electron diffraction. The high beam sensitivity of the protein nano-crystals appeared to be the rate limiting step in the data collection, not allowing orientation of the crystals (a technique used in electron diffraction studies of inorganic crystals) or a 3D data collection of a single crystal (a technique used in X-ray protein crystallography). This suggested that new approaches for data collection and data analysis needed to be developed. Optimization of the diffraction data collection, as is described in this thesis allowed high diffraction resolution (up to 2.1_) to be obtained from vitrified lysozyme crystals. An algorithm for unit cell determination of randomly oriented diffraction patterns of different crystals is presented. The method was used for the analysis of the electron diffraction data acquired from lysozyme nano-crystals. The methods for collecting and analyzing electron diffraction data from lysozyme crystals were also confirmed in the case of penicilline type nano-crystals. The motivation behind these studies and the results obtained are discussed. In this case a crystalline powder sample was subjected to electron diffraction studies. Resolutions up to 0.8_ were obtained from oxacillin crystals and up to 1_ from penicillin G crystals. The unit cell parameters found from the analysis of electron diffraction data with the algorithm presented in the previous chapter were consistent with the unit cell parameters obtained by X-ray crystallography on the same two types of penicillin. Show less
The thesis describes the application of several different magnetic resonance (MR) techniques to study the effects of the progression of disease in a transgenic mouse model of Alzheimer's. Using MR... Show moreThe thesis describes the application of several different magnetic resonance (MR) techniques to study the effects of the progression of disease in a transgenic mouse model of Alzheimer's. Using MR imaging, the amyloid plaque deposition was visualized and the plaque load quantified in the same mice as they aged. Concurrently the transverse relaxation time (T2) was measured in affected brain regions and shown to decrease over time as plaque-load increased. To study the neurochemical profile in the mouse brain brain both one- (1D) and two-dimensional (2D) MR spectroscopic techniques were employed. 1D MRS is widely used in similar research, but has limited spectral resolution. To overcome this limitation, a 2D MRS technique was implemented and optimized for use in mouse brain. This technique, L-COSY, allowed the detection of several metabolites which were not visible using standard 1D MRS techniques. This technique was subsequently used to study the effects of Alzheimer's on the neurochemical profile. Observed changes were correlated with plaque deposition. Show less
The initial damage recognizing complex in bacterial nucleotide excision repair consists of two UvrA and two UvrB molecules. Of these proteins UvrB is the main damage recognition protein and is... Show moreThe initial damage recognizing complex in bacterial nucleotide excision repair consists of two UvrA and two UvrB molecules. Of these proteins UvrB is the main damage recognition protein and is capable of recognizing various structurally unrelated types of damage. To do so, the protein must recognize a common alteration of the DNA structure induced by these different damages. For UvrB sterical hindrance of the present DNA modification prevents it from passing behind a _-hairpin structure present in the protein, thereby conferring damage recognition. Upon stalling of the protein at the site of damage in this way we show that two nucleotides become extrahelical: the nucleotide directly 3__ to the lesion and its base-pairing partner in the non-damaged strand. In contrast to other repair enzymes however the damaged nucleotide itself does not become extrahelical. Flipping in one of the two DNA strands has been shown to be important in preventing stable binding of the protein to undamaged DNA. Flipping in the other DNA strand however is required for efficient 3__ incision by UvrC, the nuclease of the system. A second incision at the 5__ side of the damage by the same protein facilitates removal of the damage-containing DNA oligonucleotide. Show less
A human consists of billions of cells. All these cells need to know in which organ they are located and what their position inside the organ is. One way to obtain this information is via morphogens... Show moreA human consists of billions of cells. All these cells need to know in which organ they are located and what their position inside the organ is. One way to obtain this information is via morphogens, small particles providing positional information. We quantitatively studied the transport of the morphogen Decapentaplegic (Dpp) in the __wing imaginal disc__ (the precursor of the wing) of fruit fly larvae. Certain cells in this disc produce Dpp, while others receive it and determine their position according to the Dpp concentration. To study Dpp transport we first developed a microscope able to follow single molecules in three dimensions in living tissue with high spatial and temporal accuracy. With this microscope we then studied the subcellular processes governing intracellular Dpp transport. We determined how long Dpp resides in different types of endosomes (a cellular compartment involved in transport). We also found that the movement of endosomes is too small to facilitate Dpp transport. Furthermore we found differences in the in- and outflow of Dpp in endosomes. This work is one of the first to quantitatively study intracellular morphogen transport. It provides new insights into growth and development of organisms. Show less
This thesis discusses the dynamical properties of high redshift infrared selected and morphologically large disk selected galaxies at redshifts between 0.7 and 2.4 and their Tully-Fisher relations.... Show moreThis thesis discusses the dynamical properties of high redshift infrared selected and morphologically large disk selected galaxies at redshifts between 0.7 and 2.4 and their Tully-Fisher relations. Most observations were done using the near infrared integral field spectrograph SINFONI of the Very Large Telescope (VLT). Show less
This thesis is concerned with two research areas in natural computing: the computational nature of gene assembly and membrane computing. Gene assembly is a process occurring in unicellular... Show moreThis thesis is concerned with two research areas in natural computing: the computational nature of gene assembly and membrane computing. Gene assembly is a process occurring in unicellular organisms called ciliates. During this process genes are transformed through cut-and-paste operations. We study this process from a theoretical point of view. More specifically, we relate the theory of gene assembly to sorting by reversal, which is another well-known theory of DNA transformation. In this way we obtain a novel graph-theoretical representation that provides new insights into the nature of gene assembly. Membrane computing is a computational model inspired by the functioning of membranes in cells. Membrane systems compute in a parallel fashion by moving objects, through membranes, between compartments. We study the computational power of various classes of membrane systems, and also relate them to other well-known models of computation. Show less
The snails__ proverbial inertness makes it an ideal subject to study the patterns and processes that lead to speciation. The land snail family Chondrinidae consists of about 70 extant species in... Show moreThe snails__ proverbial inertness makes it an ideal subject to study the patterns and processes that lead to speciation. The land snail family Chondrinidae consists of about 70 extant species in six genera. They occur throughout western and central Europe, northern Africa and as far east as Pakistan. These snails share a long and interesting evolutionary history, to the knowledge of which we contribute here. Show less
Hox genes are a very important family of transcription factors during development of vertebrate and invertebrates. This family of genes contains up to 39 Hox gene members organized in 4 clusters in... Show moreHox genes are a very important family of transcription factors during development of vertebrate and invertebrates. This family of genes contains up to 39 Hox gene members organized in 4 clusters in the genome. The main function of Hox genes is the establishment of the anteroposterior axis of the embryo. During gastrulation of the frog Xenopus laevis, Hox genes start to be expressed in the mesoderm excluding the Spemann organizer mesoderm. However, a necessary interaction between the involuting mesodermal cells and the signals from the Spemann organizer center freeze the pattern of Hox expression at that time point. Thus a temporal Hox expression is converted into a spatial Hox expression during development. Moreover, Hox gene expression within the mesoderm seems to be important for Hox expression within the neural tissue. We missexpressed several Hox genes and analyzed their phenotype within the hindbrain and more posterior neural tissue. Paralogous 1 group Hox genes are important for globally pattern the hindbrain, while Hoxc6 gene seems to very important during neurogenesis in Xenopus. Axis elongation and segmentation are liked processes during development. We showed that Hoxc6 is an important gene for proper segmentation of Xenopus embryo. Show less
Codutti, L.; Ingen, H. van; Vascotto, C.; Fogolari, F.; Corazza, A.; Tell, G.; ... ; Esposito, G. 2008
Toll-like receptors (TLRs) are receptors that continuously scour their direct surroundings for pathogen associated molecular patterns (PAMPs) of bacterial, viral or fungal origin. TLRs can be found... Show moreToll-like receptors (TLRs) are receptors that continuously scour their direct surroundings for pathogen associated molecular patterns (PAMPs) of bacterial, viral or fungal origin. TLRs can be found at cells that play a role in the immune system. Binding of the TLR with its corresponding ligand results in a signaling cascade, which initially activates the innate immune system and can eventually result in activation of the adaptive immune system. When used as well-defined adjuvants, their combination with antigen may increase the immunogenicity of the antigen itself. This so-called vaccine principle may lead to a desired long-lasting adaptive immune response or humoral memory. Currently a total of 11 TLRs are known in humans and their specific PAMPs are directly related to the location where the receptor resides. TLRs 1, 2, 4, 5, 6, 10 and 11 are situated on the outside of the cell membrane, where they come into direct contact with membrane components of pathogens. TLRs 3, 7, 8 and 9 can be found intracellularly and their ligands mainly consist of viral components released after cellular uptake and degradation of the invader. A large diversity of natural and synthetic TLR ligands is available. The newest generation of vaccines is based on synthetic TLR ligands having a well-defined chemical structure. The research described in this thesis is a first step towards the development of well-defined vaccines, able to trigger a controlled immune response by means of using TLR 2, 7 or 9. Discussed in detail are the synthesis and the immunological evaluation of ligands and conjugates aimed at activation of Toll-like receptors 2, 7 and 9. Some examples are the synthesis of a CpG DNA-peptide conjugate (TLR 9), a Pam3Cys-peptide conjugate (TLR 2) and a 7-hydro-8-oxo-adenine-peptide conjugate (TLR 7). After synthesis of the peptide (containing the antigen), several methods were applied to conjugate it to TLR2, 7 and 9 ligands. Resulting from the research performed, is that when well chosen, covalent coupling of a TLR ligand with an antigenic peptide results in an increase of cytokine production as well as antigen presentation, two of the most desired characteristics of a synthetic vaccine of this class. It is not unlikely, that future synthetic vaccines will be sharing these properties. Show less
This thesis focuses on bridging the gap between natural and artificial systems by the structural and structure-function characterization of two kinds of natural photosynthetic antenna systems, a... Show moreThis thesis focuses on bridging the gap between natural and artificial systems by the structural and structure-function characterization of two kinds of natural photosynthetic antenna systems, a pigment-protein complex i.e. the LH2 complex, and the protein-free chlorosome supramolecular light harvesters. Chlorosomes contain the largest numbers of chromophores for any antenna system known in nature and are very efficient ultra-fast light harvesters. They provide an optimal starting point for a novel class of artificial antenna arrays for ultra-rapid feeding of energy into photocatalytic devices. Show less
Protein binding can have major impact on a drug__s pharmacokinetics (PK) and pharmacodynamics (PD). At present the theoretical basis of the influence of (alterations in) plasma protein binding on... Show moreProtein binding can have major impact on a drug__s pharmacokinetics (PK) and pharmacodynamics (PD). At present the theoretical basis of the influence of (alterations in) plasma protein binding on pharmacokinetics is well-established. The role of plasma-protein binding on pharmacodynamics however has sofar not been established in a systematic manner. As such there is no scientific basis for the __free drug hypothesis__ which states that the pharmacological activity is correlated with unbound drug concentrations in plasma. The objective of the research described in this thesis is to determine, in a strictly quantitative manner, the influence of plasma protein binding on in vivo pharmacodynamics. To this end both in silico and in vivo investigations were performed using the beta-blockers as model compounds. In contrast to the PK, the free drug concentration is the main determinant of the PD under equilibrium conditions for both target and plasma protein. Moreover for the beta-blockers, the free plasma concentration appears to be the best predictor of in vivo PD. In case of a dynamic interaction, the probability of non-restrictive protein binding is (theoretically) higher with regard to the PD under certain conditions, but more extensive research is needed to confirm this statement. Show less
The thesis project is devoted to the __search of antineoplastic ruthenium/platinum/copper complexes containing also intercalator ligands; such intercalators may show efficient DNA-cleaving and DNA... Show moreThe thesis project is devoted to the __search of antineoplastic ruthenium/platinum/copper complexes containing also intercalator ligands; such intercalators may show efficient DNA-cleaving and DNA-binding properties__. The studies have been carried out using a variety of techniques. Study of the in vitro cytotoxicity against human tumour cell lines along with cellular uptake has been the pivotal point of this research. Synthetic methodologies of the new complexes have been designed to establish structure-activity relation in several series of related complexes. Platinum complexes of derivatized-phenanthroline, pyridine and pyrimidine, have been synthesized and studied in detail for their biological activity. These complexes are different in structure and in overall charges, and were studied to elucidate the effects on the activity profile. A self-activating copper-complex formed from a unique amino-phenol ligand (Hpyramol) inspired the synthesis of platinum and ruthenium analogues. Biological studies including cellular uptake, conformational changes (CD and UV) and DNA cleavage have been performed to interpret the changes in activity profile upon various metal additions. Ruthenium complexes are known as suitable candidates for anticancer (specially as antimetastatic drugs) agents. A group of ruthenium(III) complexes has been studied for their anticancer activity and their DNA-binding properties. The extensive area of homo- or heterometallic dinuclear compounds opens up an interesting challenge towards the synthesis of complexes. The studies of different combinations viz., Ru-Ru, Cu-Cu and Pt-Pt, have been performed to design new series of anticancer complexes. Show less
The design of novel anticancer agents is one of the most active fields in Medicinal Chemistry, as the number of effective drugs for treatment of cancer is still very limited. This demand for new... Show moreThe design of novel anticancer agents is one of the most active fields in Medicinal Chemistry, as the number of effective drugs for treatment of cancer is still very limited. This demand for new drugs is even higher, considering the high cancer-prevalence rate in our society. The therapeutic application of metal complexes is an under-developed area of research and basic principles in the development of metallopharmaceuticals are lacking, or at least just recently being discovered. Metal-containing agents may offer unique therapeutic opportunities. However, significant obstacles, including potential metal accumulations and toxicities, require further research before a promising metal compound may be introduced in the clinic. In particular several ruthenium and gold coordination compounds have shown promising application as anticancer agents. In these terms, this thesis project, performed in the Coordination and Bioinorganic Chemistry group in the Leiden Institute of Chemistry, comprises the design, synthesis, detailed characterization (i.e. elemental analysis, UV-Vis spectroscopy, IR, far-IR, NMR, mass spectroscopy and X-ray single-crystal structure determination) and also the biological evaluation of novel gold compounds and ruthenium compounds. The promising cytotoxic activity developed for several of these compounds and the findings from this research are providing a better understanding of chemistry of Ru(III) and Ru(II) and Au(III) coordination compounds and their structure-activity relationships and may lead to the development of improved ruthenium and gold-chemotherapeutic drugs. Show less
