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Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

L’angiogenèse est un mécanisme de néovascularisation prenant naissance a partir d’un réseau capillaire préexistant. C'est un mécanisme indispensable et hautement régulé dans des conditions physiologiques. Lorsqu'un dysfonctionnement des mécanismes du contrôle de l'angiogenèse survient, elle peut être impliquée dans le développement et la progression de maladies variées parmi lesquelles les cancers. Les principaux facteurs responsables de l’angiogenèse sont le facteur de croissance endothéliale vasculaire (vegf) et son récepteur le vegfr-2. Actuellement, de nombreuses molécules anti-angiogéniques sont en test clinique et quelques unes d’entre elles sont commercialisées. cependant, de nombreux effets secondaires ont été décrits comme par exemple des effets thrombotiques et une hypertension artérielle. Nous avons donc synthétisé de nouvelles molécules et l’évaluation de leur caractere inhibiteur sur le recepteur vegfr-2 est en cours. ces molécules ont été construites a partir d’hétérocycles tels que les 3-aminosélenophènes, les 3-amino et 2-aminothiophènes, les 4-aminothiazoles et selenazoles ; elles correspondent a des systèmes bihetérocycliques condensés : thienopyrimidines, selenolo et thiazolotriazines. / Angiogenesis, the process of new blood vessels formation, creating new capillaries from existing vasculature, is a normal process for organ development. It’s an essential and highly regulated process under physiological conditions. When a malfunction of control mechanisms of angiogenesis occurs, it may be involved in the development and progression of various diseases such as cancer. Vegf (vascular endothelial growth factor) and its receptors (mainly vegfr-2) represent one of the best-validated signaling pathways in angiogenesis. currently, many anti-angiogenic molecules are in clinical testing and some of them are marketed. However, many side effects have been described such as thrombotic effects and hypertension. we therefore synthesized new compounds and evaluation of their inhibition on vegfr-2 is under investigation. these molecules have been built from heterocycles such as 3-aminoselenophenes, 3-amino and 2-aminothiophenes, 4-aminothiazoles and selenazoles to give different polycyclic containing pyrimidinone, pyrimidine and triazine core.

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In dieser Arbeit konnten 69 neue und neuartige Koordinationspolymere sowie Komplexe mit schwefelhaltigen Liganden auf Selten-Erd-Chlorid-Basis synthetisiert und strukturell charak-terisiert werden. Durch die Umsetzung der Chloride mit dem Liganden Thiazol konnten bei Raumtemperatur, abhängig vom Ionenradius und der eingesetzten Menge Thiazol, sowohl Koordinationspolymere wie 1∞[LnCl3(thz)6]·thz (Ln = La, Ce), dimere Komplexe [Ln2Cl6(thz)8]·3(thz) (Ln = La, Ce, Pr, Nd), [Pr2Cl6(thz)8] sowie monomere Komplexe [LnCl3(thz)4]2·thz (Ln = Sm , Eu , Tb, Ho) erhalten werden. Mittels temperaturabhängiger Pulverdiffraktometrie und in-situ Infra-rotspektroskopie sowie DTA/TG-Messungen konnte exemplarisch an 1∞[LaCl3(thz)6]·thz und [Pr2Cl6(thz)8] gezeigt werden, dass stufenweise thermisch bedingt Thiazolmoleküle aus den Strukturen abgegeben werden bis hin zur Rückbildung des eingesetzten LnCl3. Unter der Vo-raussetzung, dass die flüchtige Komponente Thiazol resorbiert wird, ist daher ein Kreispro-zess denkbar. Ferner konnten zusätzlich wasserhaltige Phasen wie der vierkernige Cluster [Pr4Cl10(OH)2(thz)8(H2O)2] erhalten werden. Durch die Zugabe eines geeigneten Linkermoleküls in das Reaktionssystem aus trivalenten Lanthanidchloriden und Thiazol konnten unter solvothermalen Bedingungen eine Vielzahl an Koordinationspolymeren und Komplexen erhalten werden. Als Linker oder als end-on Ligan-den eigneten sich sowohl eine Reihe an ditopischer Pyridylliganden 4,4'-Biypridin (bipy), 1,2-Di-(4-pyridyl)ethen (dpe), trans-1-(2-Pyridyl)-2-(4-pyridyl)ethylen (tppe), 1,2-Di-(4-pyridyl)ethan (dpa), sowie die Diazine Pyrazin (pyz) und Pyrimidin (pym) oder auch Azole wie 1,2,4-Triazol (tzH) und Pyrazol (pzH). Mittels Einkristallstrukturanalyse und pulverdiffrakto-metrischer Methoden konnten die dreidimensionalen Gerüstverbindungen 3∞[LnCl3(dpa)2]·thz (Ln = Ce - Sm, Gd - Lu), die Schichtstrukturen 2∞[Ln2Cl6(bipy)3(thz)2]·thz (Ln = La, Ce), 2∞[LnCl3(tzH)2(thz)]·thz (Ln = Pr, Sm - Gd) und die strangartigen Koordinationspolymere 1∞[LnCl3(bipy)(thz)2]·thz (Ln = Pr, Nd), 1∞[LnCl3(bipy)(thz)2]·thz (Ln = Sm, Eu - Er, Yb), 1∞[Ln2Cl6(dpe)2(thz)4]·dpe (Ln = Ce, Nd), 1∞[LnCl3(dpe)(thz)2]· 0.5 (dpe) 0.5 (thz) (Ln = Sm, Gd - Dy, Er, Yb), 1∞[HoCl3(dpe)(thz)2]·thz, 1∞[La2Cl6(dpa)(thz)6], 1∞[Pr2Cl6(pyz) (thz)6], 1∞[Ln2Cl6(tzH)4(thz)2] (Ln = Pr, Sm, Gd) sowie die Komplexe [LnCl3(tppe)2(thz)2] (Ln = Nd, Tb, Ho, Er), [Ln2Cl6(pyz)(thz)6]·2(thz) (Ln = Tb, Er), [Ln2Cl6(pym)2(thz)4] (Ln = Tb , Er), [LnCl3(pzH)3(thz)2] (Ln = Pr, Gd) charakterisiert werden.   Ferner konnten die erhaltenen Verbindungen weitestgehend auf ihre photolumineszenz-spektroskopischen sowie thermischen Eigenschaften hin untersucht werden. Außerdem konn-ten auch durch direkte Schwefelkoordination an die Ln3+-Zentren eindimensionale Koordina-tionspolymere 1∞[PrCl2(amt)(py)3] (amt- = 3-Amino-5-mercapto-1,2,4-triazolat), [HNEt3]1∞[LnCl2(amt)2] (Ln = Ho, Er) und Komplexe [LnCl2(Mbim)(py)3]·py (Ln = Y, Er; Mbim = 2-Mercaptobenzimdiazolat) generiert werden / This thesis deals with the structural characterization of 69 novel coordination polymers and complexes synthesized with sulfur containing heterocyclic ligands and trivalent rare earth chlorides. Depending on the ionic radii of the used lanthanide chloride and the amount of the ligand thiazole coordination polymers as 1∞[LnCl3(thz)6]·thz (Ln = La, Ce), dimeric compounds [Ln2Cl6(thz)8]·3(thz) (Ln = La, Ce, Pr, Nd), [Pr2Cl6(thz)8] and monomeric complexes [LnCl3(thz)4]2·thz (Ln = Sm, Eu , Tb, Ho) were derived at room temperature. Using tempera-ture-dependent powder diffraction methods, in-situ IR-spectroscopy and DTA/TG measure-ments it was demonstrated that there is a stepwise, thermal induced release of thiazole molecules out of the structures to back-formation of crystalline lanthanide chloride in the cases of the coordination polymer 1∞[LaCl3(thz)6]·thz and the dimer [Pr2Cl6(thz)8]. This could be a cyclic process requiring the elusive ligand thiazole to be reabsorbed. Furthermore, hy-drous phases were also obtained like the tetranuclear cluster [Pr4Cl10(OH)2(thz)8(H2O)2]. It was possible to generate a series of various coordination polymers and complexes under solvothermal conditions adding suitable linker molecules into the reaction system of lantha-nide chloride and thiazole. Suitable linkers or end-on ligands are a range of ditopic pyridyl ligands like 4,4'-biypridine (bipy), 1,2-di-(4-pyridyl)ethene (dpe), trans-1-(2-pyridyl)-2-(4-pyridyl)ethylene (tppe), 1,2-di-(4-pyridyl)ethane (dpa), diazine as pyrazine (pyz) and pyrimi-dine (pym) as well as azole like 1,2,4-triazole (tzH) and pyrazole (pzH). By single-X-ray struc-ture determination and powder diffraction it was possible to characterize three dimensional networks 3∞[LnCl3(dpa)2]·thz (Ln = Ce - Sm, Gd - Lu), layer structures 2∞[Ln2Cl6(bipy)3(thz)2]·thz (Ln = La, Ce), 2∞[LnCl3(tzH)2(thz)]·thz (Ln = Pr, Sm - Gd) and strand like coordination polymers 1∞[LnCl3(bipy)(thz)2]·thz (Ln = Pr, Nd), 1∞[LnCl3(bipy)(thz)2]·thz (Ln = Sm, Eu - Er, Yb), 1∞[Ln2Cl6(dpe)2(thz)4]·dpe (Ln = Ce, Nd), 1∞[LnCl3(dpe)(thz)2]·0.5 (dpe) 0.5 (thz) (Ln = Sm, Gd - Dy, Er, Yb), 1∞[HoCl3(dpe)(thz)2]·thz, 1∞[La2Cl6(dpa)(thz)6], 1∞[Pr2Cl6(pyz) (thz)6], 1∞[Ln2Cl6(tzH)4(thz)2] (Ln = Pr, Sm, Gd) as well as the complexes [LnCl3(tppe)2(thz)2] (Ln = Nd, Tb, Ho, Er), [Ln2Cl6(pyz)(thz)6]·2(thz) (Ln = Tb, Er), [Ln2Cl6(pym)2(thz)4] (Ln = Tb , Er), [LnCl3(pyr)3(thz)2] (Ln = Pr, Gd). Furthermore, nearly all of the generated structures were investigated with regards to their photoluminescent and thermal properties.   Moreover, one dimensional coordination polymers 1∞[PrCl2(amt)(py)3] (amt- = 3-amino-5-mercapto-1,2,4-triazolate), [HNEt3]1∞[LnCl2(amt)2] (Ln = Ho, Er) and complexes [LnCl2(Mbim)(py)3]·py (Ln = Y, Er; Mbim = 2-mercaptobenzimdiazolate) were obtained by direct coordination of sulfur at Ln3+-centers.

Techn. Hochsch., Diss., 2000--Aachen.

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Thiopeptides are a family of antimicrobial peptides that are characterized for having sulfur-containing heterocycles, and for being highly post-translationally modified. Numerous thiopeptides have been identified; almost all of which inhibit protein synthesis in gram-positive bacteria. These intrinsic antimicrobial properties make thiopeptides promising candidates for the development of new antibiotics. The antimicrobial peptide micrococcin is a thiopeptide that is synthesized by the ribosome and undergoes several post-translational modifications (PTMs). Micrococcin is formed from a precursor peptide, TclE. TclE comprises an N-terminal leader (35-AA) that is crucial for recognition of the PTM machinery, alongside a C-terminal core sequence (14-AA) that undergoes multiple PTMs to acquire its antimicrobial activity. In the first series of modifications, the scaffold protein TclI binds the leader of TclE and presents the core of TclE to the modifying enzymes TclJ and TclN, facilitating the conversion of 6 cysteine residues into thiazoles. The work of this dissertation focuses on understanding the key interactions between the TclIJN protein complex and the precursor peptide TclE. By carrying out mutagenesis analysis on the leader peptide, I determined a minimal region of TclE that is required for thiazole installation. By doing bioinformatic analysis and copurification experiments, I determined that the TclI scaffold protein binds to the enzymes TclJ and TclN one at a time in dynamic equilibrium. I also further characterized the region of TclI that is important for coordinating these interactions and determined key residues that play a role for binding to its enzymatic partners. During my PhD, I had the opportunity to work on a few side projects that came up as I was working on plasmid construction for the Tcl project and working as a teaching assistant for the Microbial Genetics class (MMBIO360). During plasmid construction for protein expression of Tcl proteins, we recognized that there was room for improvement on transcriptional terminators, especially for the widely used T7 RNA polymerase. We engineered a set T7 terminators that are shorter and more efficient compared to previously reported T7 terminators, both in vivo and in vitro. As a teaching assistant for the MMBIO360 class, I had the opportunity to coordinate the work of undergraduate students in research-driven projects. We used the genetically tractable organism Agrobacterium fabrum to investigate flagellar motility. We carried out a near-saturating screen that led to the finding of four previously undescribed genes that are essential for motility in this organism. Another side project that also emerged from this class is investigating the genetics of streptomycin resistance in A. fabrum. Once paper from each of these three side projects are reprinted in Chapters 3, 4 and 5, respectively.

The linear peptide bisebromoamide was isolated by the Suenaga group in 2009 from the marine cyanobacterium Lyngbya sp. It exhibits antiproliferative activity at nanomolar levels against a wide range of cell lines. Current SAR data indicates that there is some flexibility in the structure with respect to stereochemistry, but the range of modifications that have been biologically tested is limited, as reviewed in Chapter 1. Bisebromoamide contains a number of non-commercial amino acids and an oxopropyl pyrrolidine moiety which had not been found in a natural product previously. Several new synthetic routes towards the non-commercial amino acid fragments have been developed, as described in Chapter 2, including two ring-closure-based approaches to the substituted proline derivative 4-methyl proline (4-MePro). While the presence of six amide bonds makes solid phase peptide synthesis (SPPS) an appealing approach to the synthesis of bisebromoamide, the 4-MePro moiety is attached to a thiazoline and it is well documented that the α-position of an amino acid will racemise, under both acidic and basic conditions, when attached to a thiazoline or oxazoline. Previous reports indicated that the methyl group of the thiazoline was not essential for biological activity and so to increase stability it was replaced with a thiazole. The total synthesis of a series of novel bisebromoamide analogues, via an SPPS approach which enables facile modification of the final structure, is described in Chapter 3. The simple and adaptable SPPS route developed lends itself to SAR studies and allows modifications such as an alanine scan, truncations and incorporation of modified proline derivatives to be achieved rapidly. The promising anticancer activity of bisebromoamide makes the biological activity of these analogues of particular interest and the results of current biological testing are reported in Chapter 4.

The research presented in this thesis introduces design criteria for development of a new type of self-contained optical biosensor. The study begins with evaluation of a dual label, fluorescence resonance energy transfer (FRET) bioassay format, and then goes on to demonstrate a signalling platform that uses an immobilized fluorescent intercalating dye so as to avoid labelling of both the target and probe strands. An extensive survey of FRET pairs that can be used to monitor hybridization events in solution and at solid interfaces was conducted in solution to provide a set of calculated Förster distances for the extrinsic labels Cyanine 3 (Cy3), Cyanine 5 (Cy5), Carboxytetramethylrhodamine (TAMRA), Iowa Black Fluorescence Quencher (IabFQ) and Iowa Black RQ (IabRQ). FRET parameters using thiazole orange (TO) intercalating dye as a FRET donor for various acceptor dye-labelled DNA conjugates in solution were determined. Limitations associated with quenching mechanisms other than those mediated by FRET motivated the development of a molecular switch that contained intercalating dye. The four binding sites associated with Neutravidin served for assembly of the switch using biotin interactions. One binding site was used to immobilize an unlabelled oligonucleotide probe. The adjacent site was used to immobilize a novel biotinylated TO derivative that could physically reach the probe. On hybridization of the probe with target, the intercalating dye was captured by the hybrid, leading to a change of fluorescence. This reversible signalling mechanism offers a method without nucleic acid labelling to detect nucleic acid association at an interface. A SNP discrimination strategy involving TO and formamide was investigated, and SNP discrimination without the requirement of thermal denaturation was achieved for multiple target lengths, including a 141-base pair PCR amplicon in solution. It was determined that formamide could also provide improvements of signal-to-noise when using thiazole orange to detect hybridization.