Yes / Organometallic complexes offer the prospect of targeting multiple pathways that are important in cancer biology. Here, the preclinical activity and mechanism(s) of action of a silver-bis(N-heterocyclic carbine) complex (Ag8) were evaluated. Ag8 induced DNA damage via several mechanisms including topoisomerase I/II and thioredoxin reductase inhibition and induction of reactive oxygen species. DNA damage induction was consistent with cytotoxicity observed against proliferating cells and Ag8 induced cell death by apoptosis. Ag8 also inhibited DNA repair enzyme PARP1, showed preferential activity against cisplatin resistant A2780 cells and potentiated the activity of temozolomide. Ag8 was substantially less active against non-proliferating non-cancer cells and selectively inhibited glycolysis in cancer cells. Ag8 also induced significant anti-tumour effects against cells implanted intraperitoneally in hollow fibres but lacked activity against hollow fibres implanted subcutaneously. Thus, Ag8 targets multiple pathways of importance in cancer biology, is less active against non-cancer cells and shows activity in vivo in a loco-regional setting. / RMP and MS funded by Yorkshire Cancer Research (pump priming grant BPP 046). IJS and AL funded by NIHR Research & Innovation Division, Strategic Project Funding 2013 and Manchester Pharmacy School Fellowship.

No description available.

The two projects described in this dissertation demonstrate the wide utility of noble metal N-heterocyclic carbene (NHC) complexes. The first project details the design of iridium NHC amino acid complexes for asymmetric transfer hydrogenation (ATH) of prochiral ketones. Iridium(I) bis-NHC complexes were found to undergo oxidative addition with a variety of alpha-amino acids, generating chiral iridium(III) complexes of the form Ir(NHC)2(aa)(H)(X) (aa = amino acid, X = halide). The complexes were screened for ATH of aryl and alkyl ketones, and optimization studies found enantioselectivity in this system was highly sensitive to the reaction temperature, NHC ligand, and amino acid. Incorporation of secondary amino acids was essential to enantioselectivity. Aryl ketones were reduced in high conversion and enantioselectivity when employing the Ir(IMe)2(L-Pro)(H)(I) catalyst in isopropyl alcohol, in some cases giving over 90% ee of the alcohol products. Density functional theory calculations were conducted in order to gain insight into the active catalytic species, and the results suggest that the high enantioselectivity of this system primarily arises from steric effects. The second project details the design of rhodium and iridium NHC piano-stool complexes featuring derivatized tetramethylcyclopentadienyl ligands (Cp*R, R = alkyl or aryl substituent) for antimicrobial applications. Complexes of the form (Cp*R)M(NHC)Cl2 (M = Rh or Ir) were synthesized by transmetallation of the NHC ligand using silver(I) oxide in the presence of the desired noble metal Cp*R dimer. The complexes were screened for biological activity against various bacteria, yeast, and fungi. Many of these compounds were highly active against Mycobacterium smegmatis, displaying minimum inhibitory concentrations (MICs) as low at 0.25 microgram per mL. Analysis of structure-activity relationships found that incorporation of the NHC ligand greatly enhances the antimicrobial properties of rhodium and iridium piano-stool complexes, more so than previously investigated diamine, amino acid, or beta-diketonato ligands. Cytotoxicity studies on one of the rhodium NHC complexes showed this compound was nontoxic towards mammalian cells at low concentrations, which strengthens the potential of these types of compounds as viable drug candidates. / Doctor of Philosophy / This dissertation describes two practical applications of a series of complexes featuring the noble metals rhodium and iridium. In all of these complexes, the metal center is bonded to one or two groups known as N-heterocyclic carbenes (NHCs). The most common structural variant of NHCs are five-membered rings. The metal is usually bonded to a carbon atom on these rings, which is flanked by two nitrogen atoms. Noble metal complexes containing NHCs are widely investigated in contemporary chemical literature for a variety of reactions, primarily because noble metals form exceptionally strong bonds with NHCs, making these complexes very stable. N-Heterocyclic carbene compounds are also fairly easy to synthesize and structurally modify, which allows fine-tuning for specific applications. The first project in this dissertation employed iridium NHC amino acid complexes for the selective production of alcohols, meaning only one structure of the alcohol product is favorably generated. This is an important transformation in the chemical and pharmaceutical industries, which often require the synthesis of highly pure products. These complexes were found to be quite successful for this application on a range of model substrates, in some cases generating as high as 95% of one alcohol product over the other. Product selectivity was found to depend on the specific structure of the NHC compound. The second project investigated the antimicrobial properties of rhodium and iridium NHC complexes. In recent years, the growing threat of antimicrobial resistance against traditional pharmaceuticals has led to an interest in the development of metal-based drugs, which may allow for metal-specific mechanisms of drug action that are not possible for commonly employed antimicrobial agents. These NHC complexes were screened for biological activity against various bacteria, yeast, and fungi. Many of the complexes displayed high activity against Mycobacterium smegmatis, comparable to those displayed by other clinical drugs such as ampicillin or streptomycin. These results were highly encouraging, as Mycobacterium smegmatis often serves as a model to study other mycobacteria.

Earth-abundant first-row transition metals have seen a renaissance in chemistry in recent years due to their relatively low toxicity and cost in comparison to precious metals. Furthermore open-shell transition metal complexes exhibit useful one-electron redox processes which contrasts to their heavier d block anologues. This thesis aims to synthesize and analyse the structure and reactivity of low-coordiante first-row transition metal complexes of from groups 7-9 with an aim to utilize these species in catalysis. The divalent compound [Co{N(SiMe3)2}2] reacts with the primary phosphines PhPH2 in the presence of an NHC ligand (IMe4) to yield the phosphinidene bridged dimer [(IMe4)2Co(µ-PMes)]2. The complex has interesting magnetic properties due to strong antiferromagnetic coupling between the two cobalt(II) centres. Increasing the steric bulk of the NHC yielded carbene-phosphinidene adducts (NHC·PAr). This transformation was shown to be catalytic. The structure and reactivity of complexes of the type [(NHC)xMn{(N(SiMe3)2}2] were investigated. The complexes exhibit similar structural properties to their iron and cobalt analogues; however their reactivity has been shown to differ. The addition of primary phosphines to complexes of the type [(NHC)xMn{N(SiMe3)2}2] yielded a range of manganese phosphide complexes. [Mn{N(SiMe3)2}2] also reacts with imidazolium salts at elevated temperatures to yield heteroleptic manganese NHC complexes. The reaction of [Mn{N(SiMe3)2}2] with IPr·HCl afforded the abnormal carbene complex [(aIPr)Mn{N(SiMe3)2}µ-Cl]2. A new monoanionic bidentate ligand is reported which has shown to be a useful ligand system to stabilize three-coordiante iron(II) complex. The reaction of [(L)Fe(Br)] with mesitylmagnesium Grignard or n-butyllithium yield the iron hydrocarbyls [(L)Fe(Mes)] and [(L)Fe(nBu)] with the latter being stable to β-hydrogen elimination. Finally [(L)Fe(nBu)] has been utilized as a pre-catalyst in the hydrophosphination of internal alkynes, showing selectivity for the E-isomeric vinylphosphine.

The ability to generate chiral building blocks is of paramount importance to organic chemists. This problem presents itself most notably at the interface of chemistry and biology, where molecules of only a single enantiomer can induce function to many biological systems. In this context, recent developments in the field of organocatalysis, most notably the employment of chiral N-heterocyclic carbenes (NHCs) have shown much promise. Our group has recently shown that one possible chiral NHC catalyzed Stetter cyclization product of a conjugated triene, a highly functionalized cyclopentenone, contains both a chiral center and an adjacent conjugated diene. This structure can be easily elaborated to a bicyclic structural motif present in some biologically active natural products from the ginkgolide family, and is difficult to access by other means. The synthesis of novel vinyl stannanes and other coupling substrates involved in the development of the aforementioned reaction discovery are described in this report.

A detailed mechanistic investigation of the previously reported ruthenium pseudo-dipeptide-catalyzed asymmetric transfer hydrogenation (ATH) of aromatic ketones was performed. It was found that the addition of alkali metals has a large influence on both the reaction rate and the selectivity, and that the rate of the reaction was substantially increased when THF was used as a co-solvent. A novel bimetallic mechanism for the ruthenium pseudo-dipeptide-catalyzed asymmetric reduction of prochiral ketones was proposed. There is a demand for a larger substrate scope in the ATH reaction, and heteroaromatic ketones are traditionally more challenging substrates. Normally a catalyst is developed for one benchmark substrate, and a substrate screen is carried out with the best performing catalyst. There is a high probability that for different substrates, another catalyst could outperform the one used. To circumvent this issue, a multiple screen was executed, employing a variety of ligands from different families within our group’s ligand library, and different heteroaromatic ketones to fine-tune and to find the optimum catalyst depending on the substrate. The acquired information was used in the formal total syntheses of (R)-fluoxetine and (S)-duloxetine, where the key reduction step was performed with high enantioselectivities and high yield, in each case. Furthermore, a new iron-N-heterocyclic carbene (NHC)-catalyzed hydrosilylation (HS) protocol was developed. An active catalyst was formed in situ from readily available imidazolium salts together with an iron source, and the inexpensive and benign polymethylhydrosiloxane (PMHS) was used as hydride donor. A set of sterically less demanding, potentially bidentate NHC precursors was prepared. The effect proved to be remarkable, and an unprecedented activity was observed when combining them with iron. The same system was also explored in the reduction of amides to amines with satisfactory results. / <p>At the time of doctoral defense, the following paper was unpublished and had a status as follows: Paper 2: Manuscript.</p>

This thesis describes selected reactivity studies of the N-heterocyclic carbene, IPr, towards a range of main group compounds. The synthesis and characterisation of sixty-three compounds, all of which incorporate IPr as a ligand in one of three coordination modes, are detailed herein. The deprotonation of IPr allowed for the isolation of an anionic source of the aIPr: ligand which was synthesised as a novel potassium salt and along with the previously reported lithium salt, was employed in reactions with group 12 and 14 bis(trimethylsilyl)amides and tetrahalides. The further chemistry of such novel products was investigated towards both electrophilic and nucleophilic reagents making use of both the pendant nucleophilic carbene functionality and the electrophilic main group centre. An alternative route to such species was investigated by the spontaneous isomerisation of IPr in the coordination sphere of group 14 tetrabromides and group 15 tribromides. The scope of this reactivity was subsequently investigated and was found to provide a simpler route to access the abnormal coordination mode of IPr. The aIPr ligand which is generated may be deprotonated by additional IPr thereby affording aIPr: ligands. The addition of halide abstracting agents allowed for the synthesis of cationic species stabilised by the coordination of either IPr or aIPr ligands. A unique, spontaneous reductive coupling of two phosphorus centres was discovered to take place upon heating a THF solution of (IPr)PBr₃. This allowed for the isolation of a bromide bridged P–P bond with reduced phosphorus centres. This facile reduction chemistry was further explored by reaction with mild reducing agents which provide access to low oxidation state phosphorus compounds in high yields. This chemistry was found to be possible (and more effective) due to the presence of the weaker phosphorus bond to bromine relative to the commonly employed chlorine ligands.

Ces dernières années, les analogues nucléosidiques ont eu un rôle majeur dans le traitement de maladies virales infectieuses tels le SIDA, les hépatites, l’herpès, la variole ou la grippe. Cependant, l’apparition de nouveaux virus ou de mutations virales ont renforcé la nécessité de développer des antiviraux plus efficaces et plus résistants. L’intensive recherche de dérivés nucléosidiques cliniquement actifs a permis l’émergence d’une multitude de nouvelles approches pour leurs synthèses. Parmi ce panel, les réactions catalysées par des métaux de transition tardifs font certainement partie des méthodes les plus importantes pour accéder à une large gamme de pharmacomodulations. Lors de ce projet de recherche, nous nous sommes intéressés à la conception, la synthèse et la découverte de nouveaux dérivés nucléosidiques en tant qu’antiviraux contre le virus de la variole. Pour ce faire, nous avons ciblé des 1,2,3-triazolo-carbanucléosides en série racémique ou énantiosélective ainsi que des nucléosides phosphonates acycliques. Dans un effort de développement et/ou d’amélioration de leurs méthodes de synthèse, nous avons également étudié la contribution de complexes au ruthénium et au cuivre contenant un carbène Nhétérocyclique (CNH) dans des réactions de métathèse croisée et de cycloaddition 1,3-dipolaire de Huisgen. Enfin, en vue d’obtenir des outils efficaces utilisables en synthèse nucléosidique, nous avons développés des nouveaux complexes au palladium portant un ligand CNH et testé leurs réactivités dans des réactions de Narylation de Buchwald-Hartwig et d’hydrogénation d’oléfines. / In the last decades, nucleoside analogues have played a major role in the treatment of viral infectious diseases, such as AIDS, hepatitis, herpes, smallpox or influenza. Nevertheless, the apparition of new or mutated viruses highlights the need of more potent and resistant antiviral therapeutics. The intense search for clinically useful nucleoside derivatives has resulted in a wealth of new approaches for their synthesis. Among them, latetransition metal-catalyzed reactions are certainly the most important methods to access variety of appealing pharmacomodulations. In this research project, we were interested in the conception, the synthesis and the discovery of new nucleoside derivatives as antiviral agents against smallpox viruses. Hence, we have targeted racemic or enantiomerically pure 1,2,3-triazolo-carbanucleosides as well as acyclic nucleoside phosphonates. In our effort into the development or/and the improvement of their synthetic methodologies, we have also studied the contribution of ruthenium and copper complexes bearing N-heterocyclic carbene (NHC) ligands in cross-metathesis and Huisgen 1,3-dipolar cycloaddition reactions. Finally, in order to obtain efficient tools useful in nucleoside synthesis, we have developed new NHC-containing palladium complexes and examined their reactivity in Buchwald-Hartwig N-arylation and olefins hydrogenation reactions.

Ce travail de thèse est consacré à la synthèse de porphyrines fusionnées à des cycles imidazolium et à l’utilisation de ces derniers comme précurseurs de ligands carbènes N-hétérocycliques (NHC). Ces composés possèdent donc deux sites de coordination, interne (le macrocycle) et externe (le ligand NHC), permettant la synthèse de complexes dinucléaires. Cette étude est principalement axée sur la synthèse de métalloporphyrines conjuguées avec des complexes d’or(I) périphériques de type [(NHC)AuCl]. En vue d’application en thérapie photodynamique (PDT), la fonctionnalisation de ces complexes par des carbohydrates (mannose) a été réalisée par substitution des ligands chlorures des complexes d’or(I) périphériques. Les tests biologiques sur cultures cellulaires montrent une nette potentialisation des propriétés photodynamiques des photosensibilisateurs comportant des ligands mannoses liés à l’or(I). Suite à cette étude, la synthèse de porphyrines fusionnées à deux cycles imidazolium a été réalisée permettant pour la première fois la synthèse de complexes trinucléaires de type Au/M/Au (M = métal interne dans la porphyrine) possédant différentes géométries. Ces composés ont ouvert des perspectives intéressantes dans le but d’obtenir des photosensibilisateurs possédant deux groupements carbohydrates à leur périphérie. De plus, il a été mis en évidence que les complexes trinucléaires de type Au/Zn/Au peuvent être utilisés comme briques de construction moléculaires pour la synthèse de polymères organométalliques en vue d’applications en (photo)catalyse. / This PhD work is devoted to the synthesis of porphyrins fused to imidazolium rings and their use as precursors of N-heterocyclic carbene ligands (NHC). Therefore, these compounds possess two coordination sites, the internal (the macrocycle) and the external (the NHC ligand) ones, allowing the synthesis of dinuclear complexes. This study is mainly centered on the synthesis of metalloporphyrins conjugated with peripheral gold(I) complexes such as [(NHC)AuCl]. In view of applications in photodynamic therapy (PDT), the functionalization of these complexes by carbohydrates was achieved through the substitution of chloride ligands of peripheral gold(I) complexes. Biological tests on cell cultures show a clear potentialization of the photodynamic properties of the photosensitizers bearing mannose ligands bound to gold(I). Following this study, the synthesis of porphyrins fused to two imidazolium rings was achieved allowing for the first time the synthesis of trinuclear species such as Au/M/Au (M = inner metal in the porphyrin core) with different geometries. These compounds open interesting perspectives in view of obtaining photosensitizers having two carbohydrates at their periphery. Moreover, it was shown that trinuclear species such as Au/Zn/Au can be used as molecular building-blocks for the synthesis of organometallic polymers in view of applications in (photo)catalysis.

L'objectif de cette thèse a été de mettre au point l'introduction d'azoles en meso d'une porphyrine par couplage d'Ullmann; Divers azoles ont pu être introduit par cette méthode avec de bons rendements, par formation d'une liaison carbone-azote. il a même été possible avec certains azotes de réaliser des doubles couplages d'Ullmann, conduisant ainsi à des 5.15-diazolyle-porphyrines. De plus, ces même conditions réactionnelles ont été utilisées pour introduire un ou deux dérivés donneurs d'électrons (carbazole, phénoxazine, phénothiazine). L'introduction d'imidazole, de triazole et de benzimidazole en meso a permis, après alkylation, d'obtenir des précurseurs de carbènes N-hétérocycles (NHC). La coordination de deux équivalents de NHC sur un sel de palladium conduit à un dimère de porphyrines via coordination exocyclique. La géométrie de coordination trans-anti autour du palladium a été confirmée par l'obtention de la structure radiocristallographique de deux complexes. Les études par électrochimie de ces complexes ont révélé une communication interporphyrinique à l'état fondamental, mise en évidence par une succession de quatre vagues monoélectroniques en oxydation. / The purpose of this thesis was to functionalize the meso position of a porphyrinWith azoles using the Ullmann coupling. Various azoles were introduced with good yieldsby using this reaction, leading to the formation of a carbon-nitrogen bond. With someazoles a double Ullmann coupling was possible, resulting in the formation of 5,15-diazolyl-porphyrins. Moreover, the same conditions were used to introduce one ortwo electron-donating groups (carbazole, phenoxazine, phenothiazine). The insertionof imidazole, triazole and benzimidazole at the meso position allowed, afteralkylation, their use as N-heterocyclic carbene (NHC). Coordination of twoequivalents of NHC to a palladium salt led to a porphyrin dimer, as a bis-carbene complex. X-Ray structures revealed that the complex’s geometry was trans-anti. Electrochemistry studies of the various dimers showed interactions between the porphyrins, highlighted by four successive oxidation peaks.