[pt] Tiossemicarbazonas e seus complexos metálicos apresentam um amplo espectro de atividades biológicas. As tiossemicarbazonas α(N)-heterocíclicas tem sido muito estudadas em razão de sua comprovada ação antitumoral. O mecanismo de ação antitumoral dessas drogas se dá pela inibição da enzima ribonucleotídeo difosfato redutase (RDR), que catalisa o ciclo de reações redox envolvido na conversão de ribonucleotídeos a desoxirribonucleotídeos durante a síntese do ADN. A forma ativa dessas drogas é o complexo de ferro. Desse modo, a obtenção de novos complexos de Fe de tiossemicarbazonas α(N)-heterocíclicas constitui uma importante estratégia para a obtenção de candidatos a antitumorais. Nesse trabalho investimos no estudo, em solução aquosa, da interação entre 2- piridinoformamida tiossemicarbazona (H2Am4DH) e seus derivados N(4)-metil (H2Am4M), N(4)-etil (H2Am4E) e N(4)- fenil (H2Am4Ph) e os íons Cu(II) e Fe(III). Esse estudo foi monitorado por espectroscopia de absorção na região do UV-vis. Para o cálculo das constantes de formação dos complexos foram levados em consideração os valores das constantes cumulativas calculadas inicialmente para as tiossemicarbazonas livres ( β HL e β H2L+). Quatro novos complexos de Fe(III) foram isolados e caracterizados: [Fe(2Am4DH)2]Cl, [Fe(2Am4Me)2]Cl, [Fe(2Am4Et)2]Cl e [Fe (2Am4Ph)Cl3]. Os valores de susceptibilidade magnética para os complexos estão na faixa de 1,36-1,66 MB. Esses valores são próximos do calculado (1,73 MB) para complexos de Fe(III), octaédricos, spin baixo. Os dados de infravermelho indicam que as tiossemicarbazonas estão coordenadas ao ferro através do sistema quelante Npy-N-S. O comportamento eletroquímico dos complexos é bastante similar, sugerindo que suas estruturas em solução são igualmente similares. A toxicidade das tiossemicarbazonas e de seus complexos de ferro frente à Artemia salina foi estudada como um pré-screening para sua ação antitumoral. Os valores de LD50 obtidos indicam que esses compostos têm atividade citotóxica, sugerindo que poderiam igualmente apresentar ação antitumoral. Além disso, os potenciais de redução FeIII/FeII observados para os complexos estão dentro da faixa ideal dos redutores celulares. Assim, se confirmada a atividade antitumoral o mecanismo de ação poderia envolver a redução FeIII/FeII por tiois celulares, como sugerido para outros complexos de ferro de tiossemicarbazonas. / [en] Thiosemicarbazones and their metal complexes present a wide range of bioactivities. It has been shown that the antitumoral action of á(N)-heterocyclic thiosemicarbazones occurs through the inhibition of ribonucleotide diphosphate reductase (RDR), a key enzyme involved in the conversion of ribonucleotides into deoxyribonucleotides during DNA syntheses. The active form of the drugs are their iron complexes. Hence the preparation of new iron complexes with á(N)- heterocyclic thiosemicarbazones constitutes an interesting strategy in designing antitumoral drug candidates. In the present work the interactions of 2- pyridineformamide thiosemicarbazone (H2Am4DH) and its N(4)- methyl (H2Am4Me), N(4)-ethyl (H2Am4Et) and N(4)-phenyl (H2Am4Ph) derivatives with Cu(II) as well as Fe(III) ions in aqueous solution were studied, monitored in the visible region by the variations of the absorption spectrum. The cumulative protonation constants â HL and â H2L+ were determined for the ligands by a potentiometric method and were used in the calculation of the complex formation constants. The iron(III) complexes [Fe(2Am4DH)2]Cl, [Fe (2Am4Me)2]Cl, [Fe(2Am4Et)2]Cl and [Fe(2Am4Ph)Cl3] were obtained and characterized. The values of magnetic moments in the 1.59-1.66 BM range are close to the calculated value of 1.73 BM, characteristic of the presence of one unpaired electron as in low spin iron(III) complexes. The infrared data for the complexes indicate coordination of the thiosemicarbazones through the Npy-N-S chelating system. The resemblance of electrochemical behaviors suggests that the structures of the complexes in solution are also very similar. The toxicity of the thiosemicarbazones and their metal complexes against Artemia salina was assayed as a prescreening of antitumoral action. The low values of LD50 obtained for the studied compounds in this assay indicate that they could present antineoplastic properties. Moreover, the determined values of FeIII/FeII redox potentials for the complexes fall in the range of cellular reductants. Therefore, if the complexes present antitumoral activity, their biochemical pathway could involve FeIII/FeII reduction by cellular thiols, as suggested previously for iron complexes of other thiosemicarbazones.

The bioavailability of iron is limited by the solubility of Fe(III) at circumneutral pH. In the High Nutrient-Low Chlorophyll (HNLC) zones of the ocean, the natural or anthropogenic addition of iron stimulates primary productivity and consumes carbon dioxide. As a result, iron fertilization has been proposed to mitigate anthropogenic carbon emissions and lower global temperatures. The natural sources of iron to the ocean are not fully constrained and include eolian depositions as well as inputs from continental shelf sediments, rivers, hydrothermal vents, and icebergs. Regardless of their source, the effectiveness of iron additions in promoting carbon fixation depends on the presence of organic ligands either natural or produced by microorganisms that stabilize or solubilize Fe(III) at neutral pH. For example, siderophores are well known to be expressed extracellularly by prokaryotes in the photic zones of the oceans to increase the bioavailability of iron. In this dissertation, the production of iron nanoparticles is demonstrated in vent fluids from the 90 North hydrothermal system. These iron nanoparticles may either catalyze the oxidation of sulfide to thiosulfate and produce a potential electron acceptor for microbial respiration or provide a source of iron that stimulates primary production at great distances from the hydrothermal vents. In addition, dissolved iron under the form of soluble organic-Fe(III) complexes is demonstrated to constitute a significant source of iron in estuarine sediments that receive large amounts of particulate iron from flocculation and precipitation at the salinity transition of this estuary. A novel competitive ligand equilibration absorptive cathodic stripping voltammetry (CLE-ACSV) technique reveals that the speciation of iron changes from largely colloidal or particulate in the upper estuary to truly dissolved organic-Fe(III) in the lower estuary. It is also demonstrated that organic-Fe(III) complexes are produced far below the sediment-water interface, suggesting that dissimilatory iron-reducing bacteria may play an important role in their production. These complexes then diffuse across the sediment-water interface and provide a significant source of iron to the continental shelf. The mechanism of reduction of iron oxides by iron-reducing bacteria is not fully understood and presents a unique physiological problem for the organism, as the terminal reductase has to transfer electrons to a solid electron acceptor. In this dissertation, it is demonstrated for the first time using random mutagenesis that the respiration of solid Fe(III) oxides by Shewanella oneidensis, a model iron-reducing prokaryote, first proceeds through a non-reductive dissolution step involving organic ligands that are released extracellularly by the cells. These soluble complexes are then reduced by the organism to produce Fe(II) and recycle the ligand for additional solubilization. Incubations with deletion mutants of the proteins involved in the respiration of Fe(III) revealed that the type-II secretion system, which translocates proteins on the outer membrane of gram-negative bacteria, is involved in the production of organic-Fe(III) complexes by secreting an endogenous iron-solubilizing ligand or a protein involved in the biosynthesis of this ligand on the outer membrane. In addition, periplasmic decaheme cytochromes produced by Shewanella appear to be involved in the mechanism of production of the endogenous organic ligand either directly or through a sensing mechanism that controls its production. In turn, two decaheme cytochromes positioned on the outer-membrane and hypothesized to be involved in the electron transfer to the mineral surface do not appear to be involved in the solubilization mechanism, suggesting either that the cells regulate the ligand production via periplasmic sensing systems or that these cytochromes are not involved in the solubilization mechanism. Altogether this research shows the production of organic-Fe(III) complexes in sediments generates a significant flux of dissolved iron to support primary production in continental shelf waters and that these complexes may be partly produced by iron-reducing bacteria. Indeed, experiments with a model organism demonstrate dissimilatory iron reducing bacteria produce endogenous organic ligands with high iron-binding constants to non-reductively solubilize iron oxides during the anaerobic respiration of iron oxides. The organic ligand is apparently recycled several times to minimize the energy cost associated with its biosynthesis. These findings demonstrate that the solubilization of iron oxides by organic ligands may be an important, yet underappreciated process in aquatic systems.

No description available.

No description available.

Reaktionen von molekularem Sauerstoff mit organischen Molekülen sind aufgrund dessen einzigartigen Triplett-Zustands Spin-verboten. Daraus resultiert eine hohe energetische Barriere für solche Reaktionen, welche ein Problem für effektive Oxidationsreaktionen zur Energiegewinnung oder Synthese unter Verwendung von Sauerstoff darstellt. Ein Weg das Spin-Verbot zu umgehen, besteht in der Verwendung von Übergangsmetallkomplexen, allen voran Eisen-Komplexen, die ungepaarte d-Elektronen aufweisen, wodurch alternative Reaktionspfade beschritten werden können. Die vorliegende Arbeit beschäftigt sich in diesem Zusammenhang mit der Sauerstoffaktivierung an verschiedenen, synthetischen nicht-Häm-Eisen-Komplexen, wobei gleichzeitig die Problematik der vollständigen vier-Elektronen-Reduktion von O2 adressiert wird. Besagte nicht Häm-Komplexe sind inspiriert durch enzymatische Vorbilder, die in der Lage sind, O2 zu aktivieren und selektiv umzusetzen, jedoch in ihrer Eigenschaft als große Biomoleküle als schwer-untersuchbar und nicht-synthetisierbar gelten. In vier Studien wird erstmals für den synthetischen nicht-Häm-Bereich die direkte Verwendung von molekularem Sauerstoff zur Gewinnung von Eisen-Sauerstoff-Intermediaten, die für Mechanismen der Sauerstoffreduktion und für Substratoxidationen relevant sind, gezeigt. Die identifizierten Eisen(IV)-Oxido-, Eisen(III)-Superoxido- und Eisen(III)-Peroxido-Kupfer(II)-Spezies wurden mit spektroskopischen Methoden wie der Mößbauer-Spektroskopie charakterisiert. Damit stellen diese untersuchten Systeme sowohl funktionale als auch strukturelle Modelle für wichtige Enzyme wie die lösliche Methanmonooxygenase, die Cytochrom-c-Oxidase oder Klasse Ia Ribonukleotidreduktasen dar. Insgesamt liefert die Arbeit damit einen weiteren wichtigen Schritt für die Adaptierung biologischer Vorbilder hin zur Entwicklung neuer künstlicher Systeme, die auf günstigem, ungiftigem Eisen sowie auf Sauerstoff als universell verfügbaren Oxidationsmittel basieren. / Due to the unique triplet ground state of molecular oxygen its reactions with organic molecules are spin-forbidden due to the unique triplet state of O2. This results in a high energetic barrier for such reactions, which poses a problem for effective oxidation reactions for energy production or the use of dioxygen in synthesis. One way to circumvent the energetic barrier of spin forbidden reactions is to use transition metal complexes, especially iron complexes, which have unpaired d-electrons and allow alternative reactions pathways. In this context, the present work deals with oxygen activation on various synthetic non-heme iron complexes, while at the same time addressing the challenging four-electron reduction of O2. The mentioned non-heme complexes are inspired by enzymes that effectively activate and selectively convert O2. However, these enzymes are considered difficult to study and cannot be efficiently synthesized as they are large biomolecules. This work consists of four studies, that show the direct use of molecular oxygen to obtain iron-oxygen intermediates, which are relevant for mechanisms of oxygen reduction and substrate oxidation. The use of dioxygen in this synthetic non-heme context is unprecedented. Different iron(IV)-oxido, iron(III)-superoxido and iron(III)-peroxido-copper(II) species were characterized using various spectroscopic methods such as Mößbauer spectroscopy. They serve as structural as well as functional models for important enzymes such as the soluble methane monooxygenase, the cytochrome c oxidase or class Ia ribonucleotide reductases. Overall, this work adds another important step on the way to adapting biological principles to the development of new artificial systems based on affordable, non-toxic iron complexes and oxygen as the universally available oxidant.

The present thesis deals with different aspects of the chemistry of iron complexes, their interaction with DNA and photo-induced cleavage of double-stranded DNA. Chapter I presents a general introduction on metal-based drugs in cancer therapy and the evolution of the transition metal complexes capable of targeting DNA leading to DNA strand scission, emphasizing particularly the photo-induced DNA cleavage activities for their potential utility in PDT. The mechanistic pathways associated with the DNA cleavage are discussed citing selected examples of compounds that are known to be efficient DNA photo-cleavers on irradiation with light of different wavelengths. Objective of the present investigation is dealt in this chapter. Chapter II deals with the synthesis, crystal structure, DNA binding and oxidative DNA cleavage activity of ternary iron(II) complexes of phenanthroline bases to explore the chemistry of iron(II) complexes towards the metal-assisted photo-induced DNA cleavage activity. Chapter III presents the synthesis and characterization of a cationic imidazo[1,5-a]pyridine derivative to explore the role of imidazopyridine moiety in the photo-induced DNA cleavage activity of the compound. Its cytotoxic effect to the HeLa cancer cell has also been studied using UV-A light of 365 nm. Chapter IV presents the synthesis and characterization of dipyridoquinoxaline (dpq) complexes of bivalent 3d-metal ions such as d6-iron(II), d7-cobalt(II), d8-nickel(II), d9-copper(II) and d10-zinc(II) to explore any specific role that is played by the transition-metal ions in exhibiting visible light-induced DNA cleavage activity. Chapter V deals with the synthesis, characterization of oxo-bridged diiron(III) complexes of phenanthrolne bases having a structural motif found in many iron-containing metalloproteins with a diiron core in the active site. DNA binding and photo-induced DNA cleavage activity of the complexes is studied. Finally, Chapter VI deals with the synthesis and characterization of oxo-bridged diiron(III) complexes having L-histidine (L-his) and N,N-donor heterocyclic bases. This chapter describes the double-strand DNA cleavage activity of [{Fe(L-his)(dpq)}2(μ-O)](ClO4)2. Rationalization of the DNA double strand break (dsb) has been made using molecular docking calculations. This chapter also deals with the site-specific protein (bovine serum albumin, BSA) cleavage activity of the complexes on UV-A light irradiation. The references have been compiled at the end of each chapter and indicated as superscript numbers in the text. The complexes presented in this thesis are represented by bold-faced numbers. Crystallographic data of the complexes, characterized structurally by single crystal X-ray crystallography, are given in CIF format in the enclosed CD (Appendix-I). Due acknowledgements have been made wherever the work described is based on the findings of other investigators. Any omission that might have happened due to oversight or mistake is regretted.

Photodynamic therapy(PDT) has recently emerged as a promising new non-invasive treatment modality for a large number of neoplastic and non-neoplastic lesions. Photoexcitation of a photosensitizing drug in the tumor tissue causes generation of reactive oxygen species which results in cell death. The current porphyrinic photosensitizers suffer a wide range of drawbacks leading to the development of the chemistry of alternative photosensitizing agents in PDT. Among them, the 4d and 5d transition metal-based photosensitizers have been explored extensively with the exception of the 3d metal complexes. The objective of this thesis work is to design and synthesize photoactive iron(III) abd cobalt(III) complexes and evalutate their photonuclease and photocytotoxic potential. Bioessential 3d metal ions provide an excellent platform for metal-based PDT drug designing as because of its varied spectral, magnetic and redox properties, with its complexes possessing rich photochemical behavior in aqueous and non-aqueous media. We have synthesized binary iron(III) complexes as netropsin mimics using amino acid Schiff bases derived from salicylaldehyde/napthaldehyde and arginine/lysine. The complexes were found to be good AT selective DNA binders and exhibited significant DNA photocleavage activity. To enhance the photodynamic potential, we further synthesized iron(III) complexes of phenolate-based ligand and planar phenanthroline bases. The DNA photocleavage activity of these complexes and their photocytotoxic potential in cancer models were studied. ROS generated by these complexes were found to induce apoptotic cell death. Ternary cobalt(III) complexes were synthesized to study the effect of the central metal atom. The diamagnetic cobalt(III) complexes were structurally dissimilar to their iron(III) analogues. Although the Co(III)/Co(II) redox couple is chemically and photochemically accessible but the Co(III)-dppz complex, unlike its iron(III)-dppz analogue, exhibited selective damage to hTSHR expressing cells but not in HeLa cells. A structure-activity relationship study on iron(III) phenolates having modified dppz ligands was carried out and it was found that electron donating group on the phenazine unit and an increase of the aromatic surface area largely improved the PDT efficiency. Finally, SMVT targeted iron(III) complexes with biotin as targeting moiety were synthesized and the in vitro efficacy of the complexes was tested in HepG2 cells over-expressing SMVTs and compared to HeLa amd HEK293 cells. The complexes exhibited higher phytocytotoxicity in HepG2 than in HeLa and cells and HEK293 cells. An endocytotic mode of uptake took place in HepG2 cells whereas in HEK293 cells, uptake is purely by diffusion. This is expected to reduce the side-effects and have less effect on cells with relatively less SMVTs. In summary, the present research work opens up novel strategies for the design and development of primarily iron-based photosensitizers for their potential applications in PDT with various targeting moieties.

Dans cette thèse nous avons eu pour but d’étudier la réactivité des complexes à bas degré d’oxydation du fer stabilisés par des ligands phosphines vis-à-vis des substrats insaturés. Cet objectif s’inscrit dans une démarche plus large d’accès à des systèmes catalytiques au fer capables de transformer de manière sélective l’éthylène, par la réaction d’oligomérisation, vers des alpha-oléfines linéaires courtes (butène-1, héxène-1, octène-1), ce qui n’a jamais été rapporté dans la littérature. Pour se faire, le passage par le mécanisme métallacyclique de transformation de l’éthylène est la voie privilégiée. Cependant, les propriétés électroniques et géométriques de ligand requises pour suivre un tel mécanisme, et en particulier son étape clé de couplage oxydant de deux molécules d’éthylène sur le centre métallique, ne sont pas clairement identifiées. Nous rapportons ici dans un premier temps la synthèse d’une bibliothèque de complexes de fer(II) et fer(III) à base de ligands phosphines présentant des propriétés électroniques et géométriques variées. Ces nouveaux complexes sont opportunément testés en tant que catalyseurs, d’une part pour la réaction d’oligomérisation de l’éthylène; mais également en tant qu’espèces réduites in situ en association avec des diènes (isoprène, butadiène) conduisant à leur polymérisation. Afin de nous rapprocher davantage de notre objectif d’accès aux espèces à bas degré d’oxydation du fer, l’emploi d’une voie de réduction en une étape et en conditions douces est rapportée; conduisant à l’isolement et la caractérisation de neuf complexes phosphorés de fer(0) à 18 et à 16 électrons. Bien qu’a priori inactifs vis-à-vis de l’éthylène ou des oléfines plus longues, nous montrons la capacité de ces complexes à promouvoir des réactions de couplage oxydant de substrats insaturés (alcynes) le couplage catalytique de l’éthylène et du butadiène et l’activation de divers composés tels que les silanes ou les halogénures d’alkyles, posant ainsi un premier jalon vers leur optimisation et application en tant que catalyseurs d’autres réactions, et potentiellement dans l’avenir, pour la transformation de l’éthylène. / In this thesis our aim was to study the reactivity of phosphine-based low-valent iron complexes towards unsaturated substrates. This goal is part of a wider approach of access to an iron catalytic system able to transform ethylene in a selective manner, by the reaction of oligomerization, towards short linear alpha-olefins (1-butene, 1-hexene, 1-octene), which is unreported in the literature. To achieve this, going through the metallacyclic mechanism of ethylene transformation is the most likely way. However, the electronic and geometrical features of the ligand required to follow this mechanism, and in particular the key step of the oxidative coupling of two molecules of ethylene to the metal center, are ill-defined. We thus report here in a first part the synthesis of a library of P-based iron(II) and iron(III) complexes bearing varied electronic and geometrical features. These novel complexes are opportunistically screened as catalysts for ethylene oligomerization on one hand, and as in situ reduced species in association with dienes (isoprene, butadiene) leading to the polymerization of the latter substrates, on the other hand. In order to get closer to our goal of access to low-valent iron complexes, the use of a one-pot reduction methodology under mild conditions is reported, leading to the isolation and characterization of nine 18- and 16-electron iron(0) complexes. Even though they do not show reactivity towards ethylene or longer olefins, we demonstrate the ability of these complexes to promote reactions involving the oxidative coupling elementary step of unsaturated substrates (alkynes), the catalytic coupling of ethylene and butadiene and the activation of various compounds such as silanes and organic halides, representing a first milestone towards their optimization and application as catalysts for other reactions, including potentially in the near future, for ethylene transformation

Les amines sont des composés essentiels en biologie, pharmacie et agriculture. La synthèse directe de tels composés constitue un enjeu majeur dans le domaine de la chimie. Le travail présenté dans ce manuscrit porte sur l’étude et le développement de synthèses intégrant le transfert de nitrène par des catalyseurs de fer pour l’obtention de composés aminés. Dans une première partie, nous avons étudié la réaction d’aziridination par plusieurs catalyseurs à base de fer sur différentes oléfines. Nous rapportons ici, comment des études mécanistiques couplées à des investigations des structures électroniques et des profils réactionnels, par des méthodes quantiques de type DFT, peuvent conduire à une complète compréhension du mécanisme, ainsi qu’au développement rationnel de nouveaux catalyseurs de fer pour la réaction d’aziridination. Nous avons pu établir que l’affinité électronique joue un rôle majeur dans ce type de transformation. Dans une seconde partie, nous avons étudié la possibilité d’intégrer la catalyse de transfert de nitrène de fer dans des processus multi-séquentiels. Nous avons pu obtenir des amidines et imidazolidines dans des réactions multicomposants via la réaction entre un substrat, un donneur de nitrène et un nitrile, le tout catalysé par le fer. Les calculs DFT ont pu confirmer le mécanisme proposer expérimentalement. Une seconde étude a pu mettre en lumière les réactions monotopes à travers la synthèse de 2-iminothiazolidines via l’ouverture de cycle d’une aziridine suivie de l’insertion d’un isothiocyanate avec de bons rendements. Ces deux types de réactions ont démontré le fort potentiel du transfert de nitrène dans des réactions multi-séquentielles et ouvrent la porte au développement de nouvelles voies de synthèses efficaces dans une chimie durable. / Amines are essential compounds in biology, pharmacy and agriculture. Therefore, their direct synthesis is a major issue in chemistry. The work presented in this manuscript focuses on the study and development of syntheses integrating nitrene transfer by iron catalysts in order to obtain amines. In a first part, we studied the aziridination reaction with several iron catalysts on different olefins. We report here, how mechanistic studies coupled with investigations of electronic structures and reactivity profiles, by quantum methods of DFT type, can lead to a complete understanding of the mechanism, as well as to the rational development of new iron catalysts for the aziridination reaction. We have been able to establish that electron affinity plays a major role in this type of transformation. In a second part, we studied the possibility to integrate iron-catalyzed nitrene transfer in multi-sequential processes. We have been able to obtain amidines and imidazolidines in multicomponent reactions via the reaction between a substrate, a nitrene donor, a nitrile and an iron catalyst. The DFT calculations were able to confirm the mechanism proposed experimentally. A second study was to highlight telescoping reactions through the synthesis of 2-iminothiazolidines via the ring opening of an aziridine followed by the insertion of an isothiocyanate with good yields. These two types of reactions have shown the strong potential of nitrene transfer in multi-sequential reactions and open the way to the development of new efficient synthesis routes in the context of green chemistry.

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