Doctor of Philosophy(PhD) / The present study deals with the synthesis and characterization of six tri-palladium complexes code named MH3, MH4, MH5, MH6, MH7 and MH8 that contained two planaramine ligands bound to the central or each of the terminal metal ions. The activity of the compounds against human cancer cell lines: A2780, A2780cisR and A2780ZD0473R, cell uptake, levels of DNA-binding and nature of interaction with salmon sperm and pBR322 plasmid DNA have also been determined. Whereas cisplatin binds with DNA forming mainly intrastrand GG adduct that causes local bending of a DNA strand, the tri-palladium complexes are expected to bind with DNA forming a number of long-range interstrand GG adducts that would cause a global change in DNA conformation. Among the designed complexes, MH6 that has two 2-hydroxypyridine ligands bound to each of the two terminal palladium ions is found to be most active. The compound also has the highest cell uptake and Pd-DNA binding levels. In contrast, MH8 which has two 4-hydroxypyridine ligands bound to each of the two terminal palladium ions is found to be least active. The results indicate that, as applied to the terminal metal centres, 2-hydroxypyridine would be more activating than 4-hydroxypyridine perhaps because of greater protection provided to the terminal centres from coming in contact with the solvent molecules. In contrast, when bound to the central metal centre, 4-hydroxypyridine appears to play a slightly greater activating role than 2-hydroxypyridine or 3-hydroxypyridine, suggesting that non-covalent interactions such as hydrogen bonding associated with the ligand rather than its steric effect may be a more important determinant of antitumour property. The results illustrate structure-activity relationships and suggest that the tri-palladium complex containing two 2-hydroxypyridine ligands bound to each of the three metal centres or the compound that contains two 2-hydroxypyridine ligands bound to each of the two terminal metal centres and two 4-hydroxypyridine ligands bound to the central metal centre, may be much more active than any of the designed complexes.

Doctor of Philosophy(PhD) / The present study deals with the synthesis and characterization of six tri-palladium complexes code named MH3, MH4, MH5, MH6, MH7 and MH8 that contained two planaramine ligands bound to the central or each of the terminal metal ions. The activity of the compounds against human cancer cell lines: A2780, A2780cisR and A2780ZD0473R, cell uptake, levels of DNA-binding and nature of interaction with salmon sperm and pBR322 plasmid DNA have also been determined. Whereas cisplatin binds with DNA forming mainly intrastrand GG adduct that causes local bending of a DNA strand, the tri-palladium complexes are expected to bind with DNA forming a number of long-range interstrand GG adducts that would cause a global change in DNA conformation. Among the designed complexes, MH6 that has two 2-hydroxypyridine ligands bound to each of the two terminal palladium ions is found to be most active. The compound also has the highest cell uptake and Pd-DNA binding levels. In contrast, MH8 which has two 4-hydroxypyridine ligands bound to each of the two terminal palladium ions is found to be least active. The results indicate that, as applied to the terminal metal centres, 2-hydroxypyridine would be more activating than 4-hydroxypyridine perhaps because of greater protection provided to the terminal centres from coming in contact with the solvent molecules. In contrast, when bound to the central metal centre, 4-hydroxypyridine appears to play a slightly greater activating role than 2-hydroxypyridine or 3-hydroxypyridine, suggesting that non-covalent interactions such as hydrogen bonding associated with the ligand rather than its steric effect may be a more important determinant of antitumour property. The results illustrate structure-activity relationships and suggest that the tri-palladium complex containing two 2-hydroxypyridine ligands bound to each of the three metal centres or the compound that contains two 2-hydroxypyridine ligands bound to each of the two terminal metal centres and two 4-hydroxypyridine ligands bound to the central metal centre, may be much more active than any of the designed complexes.

The main aim of this work was the study of bacteria capable to degrade the pyridine monocarboxylic acids. Achromobacter sp. strain JS18 capable to utilize 3-hydroxypyridine- 2-carboxylic acid was selected by screening of microorganisms hydroxylating the pyridine ring at unusual positions or transforming pyridine derivatives . The strain 5HP consuming 5- hydroxypyridine-2-carboxylic acid as a sole carbon and energy source was isolated from soil. The 16S rRNA-based phylogenetic analysis showed that the isolate belongs to Pusillimonas genus. It was found that picolinic, nicotinic and dipicolinic acids were metabolized via three distinct inducible pathways in Achromobacer sp. JS18. The appropriate biodegradation routes of these acids as well as 3-hydroxypyridine-2-carboxylic acid were was proposed. Nicotinic acid, 5-hydroxypicolinic acid and 3-hydroxypyridine induced three distinct metabolic pathways in Pusillimonas sp. 5HP cells. All pathways had the same intermediate – 2,5-dihydroxypyridine. For the first time 5-hydroxypicolinate 2-monooxygenase, which catalyzed oxidative decarboxylation of 5-hydroxypicolinic acid, was discovered, partially purified and characterized. The analysis of Sinorhizobium sp. L1 cells showed that 3-hydroxypyridine and nicotinic acid were degraded via different metabolic pathways. The Sinorhizobium sp. L1 cells converted 3-hydroxymethylpyridine to nicotinic acid. 3-hydroxypyridine and nicotinic acid induced biosynthesis of distinct isoforms of 2... [to full text] / Šio darbo metu buvo tiriamos bakterijos, galinčios skaidyti piridino monokarboksirūgštis. Netradicinėse vietose hidroksilinančių ir/ar hidroksilintų pikolino ir nikotino rūgščių skaidyme dalyvaujančių mikroorganizmų atranka leido identifikuoti Achromobacter sp. JS18 bakteriją, skaidančią 3-hidroksipiridino-2-karboksirūgštį, ir iš dirvožemio išskirti 5HP kamieną, galintį panaudoti 5-hidroksipiridino-2-karboksirūgštį vieninteliu anglies ir energijos šaltiniu. 16S rRNR geno analizės duomenimis 5HP kamienas priklauso Pusillimonas genčiai. Tai pirmoji žinoma bakterija, galinti skaidyti 5- hidroksipiridino-2-karboksirūgštį. Nustatyta, kad Achromobacter sp. JS18 bakterijose yra indukuojami trys skirtingi piridino monokarboksirūgščių skaidymo keliai. Pasiūlyti pikolino, nikotino, dipikolino rūgščių ir 3-hidroksipiridino-2-karboksirūgšties, skaidymo keliai. Pusillimonas sp. 5HP ląstelėse pirmą kartą aptikta ir dalinai išgryninta 5- hidroksipikolinato 2-monooksigenazė, katalizuojanti 5-hidroksipiridino-2-karboksirūgšties oksidacinį dekarboksilinimą, susidarant 2,5-dihidroksipiridinui. 5HP bakterijose yra indukuojami trys (3-hidroksipiridino, 5-hidroksipikolino ir nikotino rūgščių) skaidymo keliai, susidarant bendram metabolitui – 2,5-dihidroksipiridinui. Tiriant Sinorhizobium sp. L1 ląstel÷s, buvo nustatyta, kad 3-hidroksipiridino ir nikotino rūgšties skaidymas vyksta skirtingais keliais. 3-Hidroksimetilpiridinas L1 ląstelėse yra oksiduojamas iki nikotino rūgties ir skaidymas vyksta... [toliau žr. visą tekstą]

Šio darbo metu buvo tiriamos bakterijos, galinčios skaidyti piridino monokarboksirūgštis. Netradicinėse vietose hidroksilinančių ir/ar hidroksilintų pikolino ir nikotino rūgščių skaidyme dalyvaujančių mikroorganizmų atranka leido identifikuoti Achromobacter sp. JS18 bakteriją, skaidančią 3-hidroksipiridino-2-karboksirūgštį, ir iš dirvožemio išskirti 5HP kamieną, galintį panaudoti 5-hidroksipiridino-2-karboksirūgštį vieninteliu anglies ir energijos šaltiniu. 16S rRNR geno analizės duomenimis 5HP kamienas priklauso Pusillimonas genčiai. Tai pirmoji žinoma bakterija, galinti skaidyti 5- hidroksipiridino-2-karboksirūgštį. Nustatyta, kad Achromobacter sp. JS18 bakterijose yra indukuojami trys skirtingi piridino monokarboksirūgščių skaidymo keliai. Pasiūlyti pikolino, nikotino, dipikolino rūgščių ir 3-hidroksipiridino-2-karboksirūgšties, skaidymo keliai. Pusillimonas sp. 5HP ląstelėse pirmą kartą aptikta ir dalinai išgryninta 5- hidroksipikolinato 2-monooksigenazė, katalizuojanti 5-hidroksipiridino-2-karboksirūgšties oksidacinį dekarboksilinimą, susidarant 2,5-dihidroksipiridinui. 5HP bakterijose yra indukuojami trys (3-hidroksipiridino, 5-hidroksipikolino ir nikotino rūgščių) skaidymo keliai, susidarant bendram metabolitui – 2,5-dihidroksipiridinui. Tiriant Sinorhizobium sp. L1 ląstel÷s, buvo nustatyta, kad 3-hidroksipiridino ir nikotino rūgšties skaidymas vyksta skirtingais keliais. 3-Hidroksimetilpiridinas L1 ląstelėse yra oksiduojamas iki nikotino rūgties ir skaidymas vyksta... [toliau žr. visą tekstą] / The main aim of this work was the study of bacteria capable to degrade the pyridine monocarboxylic acids. Achromobacter sp. strain JS18 capable to utilize 3-hydroxypyridine- 2-carboxylic acid was selected by screening of microorganisms hydroxylating the pyridine ring at unusual positions or transforming pyridine derivatives . The strain 5HP consuming 5- hydroxypyridine-2-carboxylic acid as a sole carbon and energy source was isolated from soil. The 16S rRNA-based phylogenetic analysis showed that the isolate belongs to Pusillimonas genus. It was found that picolinic, nicotinic and dipicolinic acids were metabolized via three distinct inducible pathways in Achromobacer sp. JS18. The appropriate biodegradation routes of these acids as well as 3-hydroxypyridine-2-carboxylic acid were was proposed. Nicotinic acid, 5-hydroxypicolinic acid and 3-hydroxypyridine induced three distinct metabolic pathways in Pusillimonas sp. 5HP cells. All pathways had the same intermediate – 2,5-dihydroxypyridine. For the first time 5-hydroxypicolinate 2-monooxygenase, which catalyzed oxidative decarboxylation of 5-hydroxypicolinic acid, was discovered, partially purified and characterized. The analysis of Sinorhizobium sp. L1 cells showed that 3-hydroxypyridine and nicotinic acid were degraded via different metabolic pathways. The Sinorhizobium sp. L1 cells converted 3-hydroxymethylpyridine to nicotinic acid. 3-hydroxypyridine and nicotinic acid induced biosynthesis of distinct isoforms of 2... [to full text]

Diazonium salts are intermediates that are widely used in organic synthesis. They are typically obtained by in-situ generation of a nitrosonium ion from sodium nitrite and an acid, or by a nitrosyl transfer from an organic nitrite. Unlike extensively used aryl diazonium salts, alkyl diazonium intermediates are much less studied, due to their lower stability, and their general carcinogenicity. They usually decompose into the corresponding carbocation, affording the alcohol, halide and/or elimination product. Despite the large range of reactivity of these intermediates, diazonium salts are generally under-used, as they are potentially dangerous, especially on large scale. Solutions have been found to overcome this drawback, namely in situ formation of the diazonium species. Continuous flow is a powerful technology to handle hazardous compounds. Such a technology was recently used by our group to perform the continuous flow esterification of carboxylic acids via the diazotisation of alkylamines. The reaction proceeds in 20 minutes and is compatible with a large range of functional groups. The nitrite used in the reaction is propane-1,3-dinitrite. Notably, the reaction is compatible with hydroxy-substituted carboxylic acids. These substrates led us to study the synthesis of hydroxyesters from carboxylic acids and amino alcohols. The reaction was described in continuous flow in 30 to 60 min at 70 to 100 °C. In addition, a batch procedure in t-BuOH at 80 °C with reaction time varying from 6 h to overnight was developed. Alkyl diazonium intermediates were also used in the etherification of aryl alcohols. We developed a base-free etherification of electron-poor phenols. The reaction proceeded in batch with moderate to high yields within one hour. 2-, 3-, and 4-hydroxypyridines were also successfully reacted, as well as hydroxyquinoline and hydroxypyrimidine derivative, leading to the O-alkylated ether as the major product. Finally, N-alkylation of 5-substituted-1H-tetrazole was also achieved, and the 2N-alkylated tetrazole was obtained as a major product. A one-pot sequential 1,3-dipolar cycloaddition -diazotisation was optimized, enabling the synthesis of 2,5-disubstituted tetrazoles from nitriles, TMSN3, and alkylamine. Furthermore, different parameters governing the ratio of formation of the 1,5- and the 2,5- isomers were studied. / Les sels de diazonium sont des intermédiaires largement utilisés en synthèse organique. Ils sont généralement obtenus par génération in situ d'un ion nitrosonium à partir de nitrite de sodium et d'un acide, ou par transfert de nitrosyle à partir d'un nitrite organique. Contrairement aux sels de diazoniums d’aryle, largement utilisés, les intermédiaires diazoniums d’alkyle sont beaucoup moins étudiés, en raison de leur stabilité moindre et de leur caractère cancérigène. Ils se décomposent généralement pour former des produits résultant de la formation d’un carbocation en donnant l'alcool, l'halogénure et/ou le produit d'élimination. Malgré les différentes possibilités de réactivité de ces intermédiaires, les sels de diazonium sont généralement sous-utilisés, car ils sont potentiellement dangereux, surtout à grande échelle. Des solutions ont été trouvées pour surmonter cet inconvénient, à savoir la formation in situ des espèces de diazonium. Par ailleurs, la chimie en flux continu est une technologie puissante pour manipuler les composés dangereux. Cette technologie a récemment été utilisée par notre groupe pour réaliser l'estérification en flux continu d'acides carboxyliques via la diazotation d'amines aliphatiques. La réaction se déroule en 20 minutes et est compatible avec une large gamme de groupement fonctionnels. Le nitrite utilisé dans la réaction est le propane-1,3-dinitrite. Notamment, la réaction est compatible avec les acides carboxyliques substitués par des groupement alcool. Ces substrats nous ont conduit à étudier la synthèse d'hydroxyesters à partir d'acides carboxyliques et d'aminoalcools. La réaction a été décrite en flux continu en 30 à 60 min avec des températures allant de 70 à 100 °C. De plus, une procédure batch dans du t-BuOH à 80 °C avec un temps de réaction variant de 6 h à toute la nuit a été développée. Les intermédiaires diazoniums d’alkyle ont également été utilisés pour l'éthérification des alcools aromatiques. Nous avons développé une éthérification sans base de phénols pauvres en électrons. La réaction s'est déroulée en batch avec des rendements modérés à élevés en une heure. Les 2-, 3-, et 4-hydroxypyridines ont également été utilisées avec succès, ainsi que des dérivés d'hydroxyquinoléine d'hydroxypyrimidine, conduisant à l'éther O-alkylé comme produit majoritaire. Enfin, la N-alkylation du 1H-tétrazole 5-substitué a également été réalisée, et le tétrazole 2Nalkylé a été obtenu comme produit majoritaire. Une cycloaddition 1,3-dipolaire - diazotisation séquentielle à un pot a été optimisée, permettant la synthèse de tétrazoles 2,5-disubstitués à partir de nitriles, de TMSN3 et d'amine aliphatique. En outre, différents paramètres régissant le ratio de formation des isomères 1,5- et 2,5- ont été étudiés.