Tesi sul tema "Caged ligands"

L’objectif de ces travaux de thèse est le développement de nouveaux ligand-cages hémicryptophanes pour l’obtention de catalyseurs métalliques confinés. Ces catalyseurs seront utilisés pour l’activation bioinspirée d’O2 et la fonctionnalisation C-H en milieu confiné. Le design des cages cibles vise à introduire des ligands bioinspirés pour la coordination de métaux biologiques (Cu, Fe, Zn). La structure hémicryptophane offre une cavité hydrophobe au voisinage du site actif métallique. Cette structure vise à stabiliser les espèces actives et obtenir des réactivités différentes de celles obtenues avec les modèles ouverts correspondants. Dans ce contexte, l’objectif principale de ce travail a été d’obtenir des complexes de cuivre confinés capable d’activer l’oxygène moléculaire pour accomplir des réactions difficiles de fonctionnalisation C-H. La première partie de cette thèse consiste en étude bibliographique de (i) les précédentes applications des hémicryptophanes et (ii) les progrès récents sur les complexes bioinspirés encagés. Ensuite, nos complexes de cuivres à ligands tris(pyridyl)amine (TPA) ouverts et encagés, ont été étudiés pour l’activation d’O2 et pour des réactions non-usuelle de fonctionalisation de liaisons C-H. Nous avons ensuite préparé et étudié une nouvelle cage TPA-hemicryptophane équipée d’une cavité donneuse de liaisons hydrogène C(triazole)-H. Cette cavité fonctionnalisée vise à reproduire les cavités des métalloprotéines. Enfin, des hémicryptophanes basés sur le ligand triazacyclononane (TACN), ont été préparé pour la première fois. L’objectif de ces nouveaux ligand-cages est de contribuer au développement de complexes bioinspirés à Cu et Fe pouvant, par exemple, activer O2
This thesis aims at developing new hemicryptophane cage-ligands to obtain confined metal-based catalysts for bioinspired O2 activation and C-H bond functionalization in confined space. The design of the targeted cages aims at introducing ligands inspired from metalloproteins active sites, for coordination of biorelevant metals (Cu, Fe, Zn). Importantly, the hemicryptophane structure provide a hydrophobic cavity around the active metal core. This structure aims at stabilizing highly reactive intermediates and reaching different reactivity compare to open model complexes, devoid of cavity. In this context, a major objective of this work was to reach Cu-based bioinspired catalysts able to activate molecular oxygen for challenging C-H bond functionalization. The first part of the thesis consists in a comprehensive literature survey on (i) background of previous applications of hemicryptophane cages and (ii) recent advances in caged bioinspired complexes. The application of our open and caged Cu-complex, based on the tris(pyridyl)amine (TPA) ligand is next described. These catalysts have been used for O2 activation and unusual intramolecular C-H bond functionalization. We then prepare and studied a new TPA-hemicryptophane cage equipped with a C(triazole)-H hydrogen bonding cavity. This functionalized cavity aims at reproducing the binding cavities found in metalloproteins. Finally, hemicryptophane cages based on the triazacyclononane (TACN) ligand have been prepared for the first time. The goal of these cage-ligands is to develop new bioinspired Cu and Fe complexes that could be, for instance, used as O2 activating catalysts

Cells rely on time-dependent binding and activation by the ECM to initiate downstream signal transduction. It is unknown whether adhesion to a ligand is required throughout various cell processes, or only during a specified time period ("temporal threshold”). Current approaches to ligand presentation often comprise of static, constant densities of ligands. In contrast, natural cell adhesive interactions with ECMs exhibit spatiotemporal patterns of binding and activation. Therefore, a key to future research in controlling cell-material interactions will be the development of materials that can respond to external stimuli. The objective of this project is to engineer biomaterials that present a UV-labile caged-Arginine-Glycine-Aspartic Acid (RGD) ligand and evaluate the effects on cell activities. RGD is the minimal adhesive sequence of fibronectin. By dynamically modulating adhesive ligand presentation, the effects of temporal control on cell processes can be elucidated. In this caged-peptide, a photo-labile group adjacent to the aspartic acid residue of RGD effectively “masks” a cyclo(RGDfk) peptide. Upon UV irradiation (360 nm), the caging group is released thereby restoring the adhesive activity of the peptide. By having unparalleled spatiotemporal control of RGD ligand presentation, we demonstrated two novel tools for discovery: 1) in vivo ligand presentation to probe downstream tissue behavior and cell infiltration to biomaterial implants, and 2) in vitro ligand presentation in situ using confocal-based live cell microscopy to investigate real-time vinculin recruitment and cell traction force generation. These studies represented the first demonstration of triggerable adhesive ligand presentation in vivo and demonstrated the utility of caged-compounds for probing specific receptor-ligand responses on highly defined PEG-based hydrogels. Triggerable in vitro ligand presentation, combined with traction force microscopy, demonstrated a new research tool for investigating focal adhesion formation and downstream force generation. Taken in whole, these results provide previously unknown insights into the importance of spatiotemporal control of adhesive ligands and created novel new research platforms for future discovery.

This thesis details the synthesis and coordination chemistry of twenty-five nitrogencontaining heterocyclic ligands, nineteen of which were previously unreported compounds. These ligands were designed for use as synthons for the formation of molecular cages, so contain multiple coordination sites capable of bridging multiple metal atoms. The majority of molecular cages in the literature are formed by rigid bridging ligands, whereas the ligands studied in this research incorporate a higher level of flexibility, thereby lessening the degree of control over the self-assembly process and increasing the number of possible structures that can be formed upon reaction of these ligands with meal salts. Three of the new ligands synthesised were two-armed bridging ligands, which were reacted with a wide variety of metal salts to investigate what self-assembly products were formed. The complexes characterised include a M₃L₃ cyclic trimer, a range of coordination polymers of varying dimensionality, a range of dimeric products and a series of M₄L₆ cage-like molecular squares. However, the majority of ligands studied were three-armed, potentially tripodal compounds, which were envisaged as potential components of M₃L₂ or M₆L₄ molecular cages. The products of self-assembly of these ligands with various metals salts were shown to include a variety of discrete tri- and tetranuclear complexes, a range of coordination polymers of varying dimensionality and interpenetration, and a complex M₆L₄ assembly that appears to be a collapsed coordination cage. Unfortunately some of the ligands synthesised were shown to decompose in the presence of various metal salts, a phenomenon already identified in the literature. Analogues of these decomposition products were synthesised deliberately to identify the potential of a known tridentate ligand as a metallosupramolecular synthon. ¹H NMR spectroscopy, mass spectrometry, elemental analysis, thermogravimetric analysis and X-ray crystallography were used to study the compounds synthesised. The crystal structures of five ligands and fifty-one complexes are discussed.

Ce travail porte sur les complexes des métaux de transitions pour la catalyse de la réduction des protons en hydrogène. La nature de l'espèce catalytiquement active mise en jeu lors du processus de réduction a été étudiée par voltampérométrie cyclique afin de comprendre le rôle et le mode d'action de ces complexes. Le premier chapitre introduit le contexte et les principaux objectifs de ce travail. Le deuxième chapitre propose une étude électochimique de complexes de cobalt et de nickel à ligands bis(glyoxime) et clathrochélates en phase homogène. Leur comportement en présence d'acide et en condition réductrice est décrit et un mécanisme réactionnel associé est proposé. L'influence des ligands de la sphère de coordination sur le comportement électrochimique de ces complexes a été rationalisé par le biais de substitution des groupements présents sur les ligands bis(glyoxime) et clathrochélates. Le troisième chapitre aborde le rôle de pré-catalyseur que peuvent tenir ces complexes en condition d'électrolyse réductrice et en milieu acide. L'électrosynthèse de nanoparticules catalytiques à partir de ces complexes a mis en évidence le rôle majeur des ligands bis(glyoxime) et clathrochélates dans ce phénomène d'électrodéposition. Ces résultats montrent que ces ligands peuvent être utilisés pour contrôler la nature et l'activité de nanoparticules catalytiques pour la réduction des protons en dihydrogène. Le quatrième chapitre vise à immobiliser les complexes de cobalt à ligand clathrochélate au sein de réseaux de coordination afin d'optimiser leur activité catalytique. Malgré la faible solubilité et l'encombrement stérique de ces complexes, des synthèses en conditions très douces ont abouti à la formation de réseaux mono et bi-dimensionels à base d'ions cadmium(II).

[Truncated abstract] Chapter 1 provides an introduction to the 'sarcophagine' class of ligands and the field of metallopolymers. The synthesis, stereochemistry, physical properties and functionalisation of 'sarcophagines' and their metal complexes are discussed. A brief overview of the burgeoning field of metallopolymers is given with specific mention of the synthetic routes to pendant metallopolymers, and how these could be employed to prepared cage amine containing metallopolymers. Chapter 2 deals with the synthesis, characterisation and reactivity of cinnamylamino and styrylamido derivatives of the cage amines [Co((NH2)2sar)]3+, [Co((CH3)(NH2)sar)]3+ and [Cu((NH2)2sar)]2+. The cinnamylamino derivatives were prepared using reductive alkylation of the aforementioned amines with cinnamaldehyde. Procedures were developed to isolate the complexes without causing unwanted additions to the double bond. The cinnamylamino derivatives displayed unexpected reactivity towards a range of reducing agents, resulting in unexpected reduction of the double bond and cleavage of the cinnamyl group, but ultimately in the preparation of phenylpropylamino derivatives of [Co((NH2)2sar)]3+ and [Co((CH3)(NH2)sar)]3+. Attempts to rationalise the reactivity of the double bond have been explored based upon the physical properties and reactivity of the double bond. The styrylamido derivatives were prepared by treatment of the cage amines with 4-vinylbenzoyl chloride, and the complexes isolated in a similar manner to those of the cinnamylamino derivatives to ensure the amide linkage remained intact. Most of the complexes have been structurally characterised. ... Both the 2-thienyl and 3-thienyl derivatives of [Co((NH2)2sar)]3+ and [Co((CH3)(NH2)sar)]3+ have been prepared using reductive alkylation with the respective carboxaldehydes of thiophene. One of the optically pure isomers has been prepared. The complexes have been fully characterised including structural characterisation. Polymerisation of the thiophene-cage amine complexes was investigated under a range of chemical and electrochemical conditions, though polymerisation was never observed. Cleavage of the thienyl groups was observed when ceric ammonium nitrate in nitric acid was used as the oxidant. The attachment of oligothiophenes and mixed pyrrole-thiophene oligomers to cage amines were investigated using reductive alkylation and various pyrrole ring-forming reactions about the apical amino groups, though none of the desired complexes were isolated, reasons for the lack of reactivity were discussed. An efficient synthesis of N-(4-benzoic acid)- 2,5-di(2-thienyl)pyrrole was developed and was shown to the electropolymerisable, albeit the polymer films were non-conducting. Attempts to couple N-(4-benzoic acid)- 2,5-di(2-thienyl)pyrrole with a cage amine via its acid chloride were complicated by decomposition reactions, the nature of one of these products is discussed. Chapter 5 presents investigations into the preparation of simple complexes containing multiple cage amines using alkylation and acylation procedures with aromatic substrates. The complexes were found to exhibit some interesting electrochemical and chemical properties, demonstrating that even simple multiple cage amine species can display complicated and interesting behaviour.

Ce @ travail est consacré à l'association d'une propriété de complexation sélective et d'une propriété tensioactive au sein d'une même molécule. Nous cherchons à moduler et à contrôler chacune des ces deux propriétés indépendamment l'une de l'autre. L'approche utilisée est la synthèse de molécules dibloc : Les molécules cages tensioactives développées résultent du greffage covalent d'un ou plusieurs motifs tensioactifs glucosyles sur un composé macro cyclique ether-couronne azote. Deux molécules cages tensioactives ont été étudiées. Elles diffèrent par le nombre de motifs tensioactifs greffes. Leurs propriétés de complexation vis-à-vis des ions na + et k + ont été mises en évidence par spectrométrie de masse. Nous avons caractérisé les micelles formées par ces différents tensioactifs par ajustements simultanés des spectres de diffusion de rayons-x et de neutrons aux petits angles. Lorsque la longueur de sa chaîne aliphatique croit, le motif tensioactif forme des agrégats ellipsoi͏̈daux puis cylindriques et enfin des bicouches. Les molécules cages tensioactives forment par contre des micelles ellipsoi͏̈dales. Ces micelles sont très peu modifiées lorsqu'un cation est complexe par le macro cycle et semblent peu dissociées de leurs contre-ions. Leur forme et leur taille sont contrôlées par des contraintes stériques, imposées par la nature et le nombre de motifs tensioactifs ainsi que par le macro cycle. Enfin, un montage de flottation ionique a été réalisé à une échelle adaptée à une faible quantité de produit. La technique de flottation consiste à faire mousser un tensioactif dans une colonne. Elle permet d'étudier les équilibres d'adsorption d'ions à une interface eau/air recouverte d'un tensioactif. Il peut s'agir de l'adsorption de contre-ions d'un tensioactif ionique ou également de la complexation du cation par un ligand macro cyclique situe à l'interface. Nous avons alors appliqué cette technique à une molécule cage tensioactive pour évaluer ses propriétés extractantes.

Neurodegenerative disorders, including Alzheimer's and Parkinson's disease, and the development of neuroprotective agents have received significant research attention in recent years. Development of novel imaging techniques to study the biological mechanisms involved in the progression of these disorders have become an area of research interest. The design of novel small molecule imaging probes in combination with modem imaging techniques may provide information on neuroprotective binding site• interactions and would assist in the design of novel biological assay methods. Techniques to visualize physiological or pathophysiological changes in proteins and living cells have become increasingly important in biomedical sciences, especially fluorescent techniques. Fluorescent ligands in combination with sophisticated fluorescent imaging technologies are useful tools to analyze and clarify the roles of biomolecules in living cells, affording high spatial and temporal resolution. This study is based on the development of polycyclic fluorescent ligands, which may be used in the study of receptor-ligand and/or enzyme-ligand interactions, utilizing these fluorescently labeled ligands in combination with fluorescent imaging techniques. Fluorescent conjugates with high affinity for the• N-methyl-D-aspartate (NMDA) receptor, voltage gated calcium channels (VGCC) and/or the nitric oxide synthase (NOS) enzyme were designed and synthesised with the aim to directly measure binding of these novel molecules to receptors and/or enzymes. The first goal was to develop fluorescent ligands that exhibit similar inhibitory activity on NOS compared to the well-known selective neuronal NOS inhibitor 7-nitroindazole (7-NI). Polycyclic compounds, including amantadine and pentacycloundecane derivatives, were conjugated to fluorescent moieties that resemble the structure of 7-NI. It was thought that the lipophilic nature of the polycyclic compounds would increase the activity of the fluorescent moieties by facilitating increased blood brain barrier permeability and penetration through cell membranes. This would also potentially increase the selectivity of the novel conjugated compounds as selective neuronal NOS inhibitors, similar to 7-NI. The results from the NOS inhibition studies indicated that the novel fluorescent conjugates (5-14) inhibited the NOS enzyme at micromolar concentrations. Although none of the novel fluorescent polycyclic compounds were found to be more potent than 7-NI (IC50 = 0.11 11M), the indazole pentacyclorindecane (5), the coumarin-adamantane (7), the dansyl-adamantane (8), and the cyanoisoindole-adamantane (11) conjugates, exhibited IC5o values below 1 uM. These compounds could possibly be used as molecular probes in the development of high-throughput screening or competitive NOS displacement assays. Further studies on isoform selectivity will elaborate on the potential of these compounds as fluorescent molecular probes. The aforementioned fluorescent derivatives were further developed resulting in a series of novel fluorescent polycyclic conjugates with potent NOS inhibition indicating the potential of these compounds as neuroprotective agents. Due to the polycyclic structure's inherent inhibitory activity towards the NMDA receptor and VGCC we evaluated these derivatives as possible multifunctional neuroprotective agents acting on various neuroprotective targets. In the biological studies it was observed that four adamantane fluorescent compounds (7, 8, 10, 11) exhibited a high degree of inhibitory activity against the NOS enzyme and NMDA receptor and blocked VGCC. The fluorescent compounds were further able to scavange detrimental neurodegenerative free radicals. In silica studies also predicted a high degree of oral bioavailability and that these novel compounds should be effectively transported across the blood brain barrier. Taking the positive findings on the inhibition of the NMDA receptor and VGCC activity of the novel fluorescent polycyclic ligands into account we focused on the expansion of this series. This resulted in the synthesis of a series of fluorescent derivatives utilizing adamantane-3-aminopropanol as an intermediate to extend the chain length between the adamantyl and fluorescent moieties, to potentially reduce sterical hindrance and increase activity. These novel adamantane-3-aminopropanol fluorescent ligands were also evaluated for inhibition of the NMDA receptor and VGCC. The coumarin-, dansyl- and cyanoisoindole adamantane-3-aminopropanol fluorescent conjugates (15, 16, 19) displayed significant VGCC inhibition, with the dansyl (16) and di-nitrobenzene (20) fluorescent derivatives exhibiting NMDA receptor antagonistic activity. All these compounds showed improved activity when compared to known NMDA receptor and VGCC inhibitors in this class. Generally it was observed that the increased chain length analogues had improved VGCC inhibition and NMDA receptor activity when compared to their directly• conjugated counterparts. This led to the conclusion that an increase in chain length might indicate deeper immersion into the NMDA receptor and VGCC which may be necessary for stronger interaction with their putative binding sites. The dansyl analogue, N-[3-(1-adamantylamino)propyl]-5- dimethylaminonaphthalene-1-sulfonamide (16), was further used as a fluorescent NMDA receptor ligand in a fluorescent competition assay, utilizing known NMDA receptor inhibitors to demonstrate the possible applications of these novel fluorescent analogues and their benefit over the use of hazardous and expensive radioligand binding studies. Further investigation on the application of these derivatives, especially on the NOS enzyme and the NMDA receptor, will develop their potential as fluorescent ligands in the study of neurodegeneration and may also yield novel therapeutic agents against neurodegenerative disorders.
PhD (Pharmaceutical Chemistry), North-West University, Potchefstroom Campus, 2012

La méthodologie d'auto-assemblage assisté par des métaux (typiquement Pt et Pd) a permis la préparation d'un grand nombre de polygones (triangle, carré,. . . ) et de polyèdres (cubes, prismes,. . . ) moléculaires. Néanmoins, très peu à ce jour sont électro-actifs et aucun ne présente une cavité enrichie en électrons. Cette thèse a pour objet la synthèse et la caractérisation des premiers exemples de cages moléculaires riches en électrons auto-assemblées à l'aide de complexes métalliques, ainsi que l'étude de leur aptitude à complexer différents substrats moléculaires. Ces nouvelles structures discrètes auto-assemblées incorporent des parois redox-actives basées sur le motif tétrathiafulvalène (TTF), unité bien établie comme modulateur redox d'architectures moléculaires / supramoléculaires variées. Dans ce contexte, plusieurs voies de synthèse visant à préparer des ligands inédits associant cette unité (ou ses dérivés BPTTF ou exTTF) à deux ou quatre motifs coordinants ont été développées. Les propriétés électroniques (spectroscopie, voltammétrie cyclique) et structurales (calcul DFT, diffraction RX) de ces composés ont été étudiées, et permettent d'anticiper les propriétés des auto-assemblages correspondants. La méthodologie d'auto-assemblage métalla-dirigé a été appliquée à ces ligands à l'aide de complexes métalliques variés. Un triangle moléculaire a été caractérisé et démontre une excellente aptitude à complexer une molécule électrodéficiente complémentaire (C60). Les ligands tétratopiques ont par ailleurs permis l'accès aux premiers exemples de cages (prismes, cubes. . . ) à base TTF (ou dérivés), dont les cavités sont tapissées de motifs riches en électrons. Ces structures ont fait l'objet d'études spectroscopiques variées (dont DOSY, FTICR,. . . ) et pour certaines, de caractérisations par diffraction de rayons-X sur monocristal. Enfin, l'aptitude de ce nouveau type de cavités à inclure des substrats moléculaires variés est discutée
The metal-driven self-assembly methodology has afforded a large panel of molecular polygons (triangle, square,. . . ) and polyhedrons (cubes, prisms,. . . ). Nevertheless, very few of them are electro-active and none presents an electron-rich cavity. The topic of this thesis concerns the synthesis and characterization of the first examples of metal-based self-assembled electron-rich molecular cages, as well as the study of their capacity to include various molecular substrates. These new self-assembled discrete structures incorporate redox-active walls based on the tetrathiafulvalene (TTF) moiety, a well-established unit known as a redox modulator for varied molecular / supramolecular architectures. On this ground, several synthetic routes to various new ligands incorporating this unit (or derivatives such as BPTTF or exTTF) and two or four coordinating moieties have been developed. Electronic properties (spectroscopy, cyclic voltammetry) as well as structural features (DFT calculation, X-ray diffraction) of these systems have been determined and allow to anticipate their self-assembly behavior. The metal-driven self-assembly methodology was applied to these ligands from various metal complexes. A molecular triangle was characterized and demonstrates an excellent ability to bind a complementary electrodeficient molecule (C60). In addition, tetratopic ligands allowed the access of the first examples of TTF-based cages (prisms, cubes,. . . ), with electron-rich cavities. These architectures have been characterized through various spectroscopic methods (eg DOSY, FTICR,. . . ) and in some cases by single crystal X-ray diffraction. Finally, the capacity of this new type of cavities to include varied molecular guests is discussed

La méthodologie d'auto-assemblage assisté par des métaux (typiquement Pt et Pd) a permis la préparation d'un grand nombre de polygones (triangle, carré, ...) et de polyèdres (cubes, prismes, ...) moléculaires. Néanmoins, très peu à ce jour sont électro-actifs et aucun ne présente une cavité enrichie en électrons. Cette thèse a pour objet la synthèse et la caractérisation des premiers exemples de cages moléculaires riches en électrons auto-assemblées à l'aide de complexes métalliques, ainsi que l'étude de leur aptitude à complexer différents substrats moléculaires. Ces nouvelles structures discrètes auto-assemblées incorporent des parois redox-actives basées sur le motif tétrathiafulvalène (TTF), unité bien établie comme modulateur redox d'architectures moléculaires / supramoléculaires variées. Dans ce contexte, plusieurs voies de synthèse visant à préparer des ligands inédits associant cette unité (ou ses dérivés BPTTF ou exTTF) à deux ou quatre motifs coordinants ont été développées. Les propriétés électroniques (spectroscopie, voltammétrie cyclique) et structurales (calcul DFT, diffraction RX) de ces composés ont été étudiées, et permettent d'anticiper les propriétés des auto-assemblages correspondants. La méthodologie d'auto-assemblage métalla-dirigé a été appliquée à ces ligands à l'aide de complexes métalliques variés. Un triangle moléculaire a été caractérisé et démontre une excellente aptitude à complexer une molécule électrodéficiente complémentaire (C60). Les ligands tétratopiques ont par ailleurs permis l'accès aux premiers exemples de cages (prismes, cubes...) à base TTF (ou dérivés), dont les cavités sont tapissées de motifs riches en électrons. Ces structures ont fait l'objet d'études spectroscopiques variées (dont DOSY, FTICR, ...) et pour certaines, de caractérisations par diffraction de rayons-X sur monocristal. Enfin, l'aptitude de ce nouveau type de cavités à inclure des substrats moléculaires variés est discutée.

Coupling homogeneous catalysts to dendrimers with rigid nuclei is one possible strategy to recycle these compounds in an industrial environment. During this study attempts were made to attach the well-defined ruthenium carbene complex 2 to the alicyclic compound 1A. To achieve this goal attempts were made to functionalise 1A with anime groups to facilitate the attachment of phosphine groups. The catalyst 2 would then be attached through a phosphine exchange reaction. Oximes were used as precursors in attempts to prepare cage amines from 1A. For this purpose, the dioxime 28 was prepared from 1A. Reduction of 28 was unsuccessful. Molecular modelling showed that the lobes of the LUMOs of the oxime carbon atoms of 28 do not protrude from the total electron density of this molecule. This observation indicates that 28 would probably not react with nucleophiles, such as the hydride ion. Molecular modelling was used to probe the unreactive nature of oxime 28. The probe revealed that the imide ring deactivates the oxime groups in this compound. Based on these results, attempts were made to change the carbon framework of 1A to eliminate unwanted interaction between the carbonyl groups. Clemmensen reduction of 1A did not yield the expected ketol 40, but gave a mixture of 62 and 63. Extended reaction times yielded 63 only. Reduction of 1A with zinc and acetic acid produced a mixture of 62 and 40 that could not be separated. Consequently, the applicability of 62 as a possible dendrimer nucleus was investigated. Compound 62 was obtained by oxidisation of the diol 63 with sodium periodate. Attempts to synthesise the dioxime 69 from 62 failed and only the mono oxime 71 was obtained. Reduction of 71 with lithium aluminium hydride was unsuccessful. Molecular modelling revealed that the oxime carbon atom does not have a LUMO and that the carbonyl carbon atom would probably be unreactive towards nucleophiles. Several other attempts were made at reducing the oxime 71 to an amine. None of these attempts met with any success. The reason for the unreactive nature of 71 is less clear than in the case of 28. Failure to produce a cage amine from 1A or derivatives of 1A meant failure in functionalising the cage system with phosphine groups and coupling the Grubbs-I catalyst. It seems that cage compounds based on 1A are generally not suitable as starting materials for amine-functionalised dendrimer nuclei.
Thesis (M.Sc. (Chemistry))--North-West University, Potchefstroom Campus, 2011.

Dans une premiere partie, la preparation de nouveaux phosphites bicycliques chiraux est decrite. Dix phosphites cages ont ete prepares a partir de l'acide glutamique en six etapes. Les rendements sont bons et les stereoselectivites sont excellentes. En fonction de la configuration absolue de l'acide glutamique utilise (r ou s), l'une ou l'autre des deux paires de diastereoisomeres (rs et rr ou sr et ss) est obtenue selectivement. Ces phosphites isomeres (rs, rr, sr et ss) peuvent obtenus enantiomeriquement et diastereoisomeriquement purs en separant les hydroxylactones rs et rr ou sr et ss obtenues au cours de la quatrieme etape. Cette strategie a ete appliquee a d'autres amino acides : la (s)-serine et la (s)-methionine. De nouveaux phosphites derives du (-)-8-phenylmenthol ont egalement ete prepares avec de bons rendements. Dans une seconde partie, les phosphites dont nous decrivons la synthese ont ete utilises comme ligands pour l'addition conjuguee enantioselective d'organozinciques sur des enones. Les phosphites bicycliques de configuration relative erythro ont conduit a des inductions moyennes lors de l'addition du diethylzinc sur la cyclohexenone en presence d'une quantite catalytique de trifluoromethanesulfonate de cuivre(ii). Les phosphites issus de l'acide (s)-glunamique conduisent majoritairement a la (s)-3-ethylcyclohexanone. Par ailleurs, les phosphites issus de l'acide (r)-glutamique conduisent majoritairement a la (r)-3-ethylcyclohexanone. D'autres dialkylzincs primaires peuvent etre utilises et donnent des resultats analogues. Les essais effectues sur des cetones non cycliques ont conduits a des inductions tres faibles. Enfin, dans tout les cas, les phosphites bicycliques de configuration relative threo, comme les phosphites derives du (-)-8-phenylmenthol, n'ont conduits qu'a de tres faibles inductions.

L'élaboration de diodes électroluminescentes organiques (OLEDs) est un défi technologique majeur de ce début de siècle. Afin d'optimiser l'efficacité de ces dispositifs, des complexes de métaux de transition luminescents peuvent être incorporés dans la couche émettrice. Dans ce contexte, la chimie de coordination de complexes de métaux d10 a été étudiée pour la préparation de composés phosphorescents homo- et hétéroleptiques à partir de divers ligands diazotés et diphosphorés. Parmi les complexes préparés, plusieurs présentent un excellent potentiel pour l'élaboration de diodes électroluminescentes. La chimie de coordination de métaux d10 permet également de préparer différents types d'édifices supramoléculaires. A partir d'un complexe cuivreux et de différents ligands nitriles, il a été possible d'obtenir des polymères de coordination et des composés macrocycliques. Ces édifices ont été caractérisés par le biais d'une étude systématique à l'état solide par diffraction des rayons X, ainsi qu'en solution par spectroscopies RMN et UV-visible. La préparation de nanostructures riches en fullerène est un autre thème de recherche de notre groupe pour l'élaboration de matériaux intéressants. Dans le cadre de ce travail, des branches dendritiques incorporant le fullerène ont été utilisées pour fonctionnaliser des assemblages supramoléculaires préparés à partir du cuivre(I) ou pour synthétiser des cages d'étain entourées de six branches dendritiques par condensation d'un acide carboxylique avec un acide stannique
The elaboration of organic light emitting diodes (OLEDs) is a technological challenge of this early century. In order to optimize the efficiency of these devices, luminescent transition metal complexes can be incorporated in the emitting layer. In this context, coordination chemistry of d10 metal complexes was studied for the preparation of phosphorescent homo- and heteroleptic compounds starting from N- and P- ligands. Some of these complexes show excellent properties for the elaboration of light emitting diodes. Furthermore, coordination chemistry of d10 metal allows the preparation of different supramolecular structures. Starting from a copper (I) complex and different nitrile ligands, it is possible to obtain coordination polymers and macrocyclic compounds. These structures were characterized systematically in the solid state by X-ray crystallography and solution by NMR and UV-vis spectroscopy. The preparation of fullerene-rich nanostructures is another topic of our research group to elaborate advanced materials. In the context of this work, dendritic branches incorporating fullerene units were used in order to functionalize supramolecular assemblies prepared from copper(I) complexes, or to synthesize organooxotin nanoclusters surrounded by six dendritic branches from condensation of a carboxylic acid and a stannic acid

Cette thèse décrit principalement la conception de ligands et la synthèse de leurs complexes d’or fonctionnels pour la catalyse. Des ligands thioéther ont été développés pour accéder aux complexes d'or (III) chlorure qui peuvent être photoréduits en l’or (I), en utilisant la lumière UV ou visible. Ces deux espèces d'or ont été exploitées en catalyse homogène en tant qu’acides de Lewis, lors d’une réaction ‘one pot’ de cyclisation en cascade conduisant à une composé polyhétéroaromatique fusionné. Des ligands de phosphine ont aussi été élaborés puis les complexes d'or(I) chlorure correspondants ont été greffés sur des nano-objets de silices pour la catalyse hétérogène. L’induction chirale des hélices de silices chirales sur les complexes d’or a été observée par dichroïsme circulaire. En présence de sels d’argent, les catalyseurs d’or immobilisés de manière covalente ont montré une réactivités élevée et une bonne recyclabilité lors de réactions de spirocyclisation d’esters d’aryl alkynoates. D’autres ligands thioéther encombrés à base de 9,10-diphénylanthracène (DPA) ont été utilisés pour former des complexes d’argent, dont l’auto-assemblage peut être ajustée en fonction de la nature de l’anion associé à l’argent et en prolongeant la longueur de la chaîne de coordination. Leur forte activité en catalyse a été démontrée au cours de deux reactions tandem d’addition/ cycloisomérisation d’alcynes en utilisant une charge catalytique de 0.5 à 1 % mol. Finalement, la réactivité régiosélective et réversible du 9,10-DPA vis-à-vis de l’oxygène singulet a été exploitée sur deux systèmes moléculaires à propriétés commutables: d’une part, une cage hexa-imine commutable auto-assemblée comportant trois piliers DPA qui montre une affinité pour les ions métalliques et d’autre part, différents sulfoxydes chiraux positionnés sur la plateforme DPA dont les propriétés chiroptiques sont conçues pour être commutables
This thesis describes the use of ligand design to achieve functional gold complexes for catalysis. Thioethers ligands were designed to form gold(III) chloride complexes which can be photoreduced to gold(I) using UV or visible light. Both gold species catalytically active lewis acids that can be used in a ‘one pot’ cascade cyclization reaction leading to a fused polyheteroaromatic compound. Functionalized phosphine ligands were also elaborated and the corresponding gold(I) chloride complexes smoothly grafted onto silica nano-objects for heterogeneous catalysis. Chiral induction from the chiral silica helices to the surface-bound gold complexes was confirmed using circular dichroism. In the presence of a silver salt, the covalently bound gold catalysts exhibited high reactivity and good recyclability in the dearomative spirocyclization reaction of aryl alkynoate esters. 9,10-Diphenylanthracene (DPA) based thioether ligands were also used to form silver complexes whose self-assembly can be tuned by the nature of the counteranion or by extending the length of the coordination chain. Their activity in homogeneous catalysis was confirmed in two tandem addition/cycloisomerization of alkynes using 0.5-1 mol% of catalytic loading. Based on the reversible covalent transformation of DPA upon cycloaddition of singlet oxygen, two systems demonstrating switchable properties were developed: a switchable [2+3] imine cage with three DPA pillars exhibiting an affinity for metal ions, and DPA-based chiral sulfoxides designed to exhibit tunable chiroptical properties

Durant ces dernieres annees, de nombreuses proteines fer-soufre ont ete decouvertes dont le site actif est relie a l'apoproteine par des ligands non-cysteinyles ; elles presentent des proprietes spectroscopiques et electrochimiques particulieres, liees a la nature des acides amines impliques dans la coordination du cur fer-soufre. Pour modeliser la coordination d'histidines sur les centres fer-soufre, nous avons prepare des agregats a ligands imidazoles neutres. Notre demarche synthetique fait intervenir des centres fer-soufre deja formes, a ligands halogenures, sur lesquels nous realisons une reaction d'echange de ligands. De premiers essais de coordination de ligands azotes neutres sur des agregats 2fe-2s nous ont amenes a definir certains criteres pour les ligands a cycles imidazoles en vue de leur coordination. L'utilisation de ces ligands nous a ensuite permis d'isoler de nouveaux composes fer-soufre qui presentent des proprietes oxydo-reductrices proches de celles des proteines fer-soufre a ligands histidines. Enfin, nous avons etudie la reactivite des ligands imidazoles par rapport a des agregats 4fe-4s

Quinoxaline-functionalized, cage-annulated oxa- and thiacrown ethers have been synthesized as possible specific metal host systems. The synthesis and characterization of quinoxaline-functionalized, cage-annulated oxa- and thiacrown ethers have been described. The characterization of these host systems have been fully achieved in solution by using various techniques such as IR, 1H NMR, and 13C NMR spectroscopic methods, high-resolution mass spectrometry (HRMS), elemental microanalysis, and X-ray crystallographic analysis in case of one quinoxaline-functionalized, cage-annulated oxacrown ether compound. The synthesis of the diphosphine ligand 2,3-bis(diphenylphosphino)-N-p-tolylmaleimide (bmi) is described. The substitution of the MeCN ligands in the activated cluster 1,2-Os3(CO)10(MeCN)2 by the diphosphine ligand bmi proceeds rapidly at room temperature to furnish a mixture of bridging and chelating Os3(CO)10(bmi) isomers and the ortho-metalated product HOs3(CO)9[μ-(PPh2)C=C{PPh(C6H4)}C(O)N(tolyl-p)C(O)]. Thermolysis of the bridging isomer 1,2-Os3(CO)10(bmi) under mild conditions gives the chelating isomer 1,1-Os3(CO)10(bmi), whose molecular structure has been determined by X-ray crystallography. The kinetics for the ligand isomerization have been investigated by UV-vis and 1H NMR spectroscopy in toluene solution over the temperature range of 318-348 K. On the basis of kinetic data conducted in the presence of added CO and the Eyring activation parameters, a non-dissociative phosphine migration across one of the Os-Os bonds is proposed. Orthometalation of one of the phenyl groups associated with the bmi ligand is triggered by near-UV photolysis of the chelating cluster 1,1- Os3(CO)10(bmi).

Metallosupramolecular chemistry involves the construction of nanoscale molecular assemblies by reacting metal atoms with bridging organic ligands. The metal atoms act as a type of molecular ‘glue’ binding together the organic ligands in specific orientations. Thus, appropriate combinations of metal ions and ligands lead to the controlled self-assembly of interesting one-, two- and three-dimensional molecular aggregates. This thesis details the preparation of a range of novel flexible bridging heterocyclic ligands using conventional organic synthesis, and then explores their reactions with a variety of transition metal precursors. By varying the nature of the organic ligand and the transition metal precursor, new and exciting supramolecular topologies and architectures can be formed. A total of forty-eight ligands were synthesised in this work, forty-seven of which are new compounds. The majority of the ligands synthesised were based around commercially available bisphenol cores. All forty-eight of the ligands had nitrogen heterocyclic groups as coordinating units. The ligands discussed in this thesis can be divided into three main sections. The first involves the synthesis and coordination chemistry of two-armed ligands based around the Bisphenol A, Bisphenol Z and Bisphenol AP cores. The second section describes the synthesis and coordination chemistry of the larger Bisphenol P and Bisphenol M based two-armed bridging ligands. The third section describes the synthesis and coordination chemistry of various multi-substituted ligands, including tripodal ligands based around a trisphenol core, four-armed ligands and six-armed ligands. The two-armed bisphenol based ligands proved very successful as synthons in metallosupramolecular chemistry and produced many products with a variety of different metal atoms. The complexes characterised included discrete dimeric products, coordination polymers and a number of helicates, including a dinuclear quadruply-stranded helicate. Multi-armed ligands are topical, because they have multiple coordination sites that are capable of binding and bridging multiple metal atoms. Such coordination can lead to the construction of cage-like species and complicated networks. A series of three-armed ligands based around a trisphenol core were synthesised with the intention to use these to form such species on coordination with appropriate metal salts. Indeed, one of the products of self-assembly was an interesting M₃L₂ cage. Various other multi-armed ligands were also investigated. The ligands and complexes in this thesis were characterised by a variety of structural techniques, such as ¹H NMR, ¹³C NMR, mass spectrometry, elemental analysis and X-ray crystallography when crystals were obtained. The crystal structures of twenty-seven ligands and forty-three complexes are described.

Dissertação de Mestrado em Bioquímica apresentada à Faculdade de Ciências e Tecnologia
Recetores acoplados à proteína G são alvos terapêuticos-chave para muitas condições patológicas. Estudos demonstraram que os recetores A2A de adenosina (A2AR) e D2 de dopamina (D2R) acoplados à proteína G formam heterómeros A2AR-D2R no estriado. A estequiometria deste heterómero encontra-se alterada na doença de Parkinson (DP) e a sinalização mediada pelos recetores A2A pode ser promovida. Deste modo, os recetores A2A são o alvo farmacológico de eleição na DP que mais tem recebido atenção nos últimos anos. No entanto, a ubiquidade deste recetor tem dificultado a seletividade no tempo e no espaço de fármacos baseados em adenosina, levando à diminuição do seu efeito terapêutico. A fotofarmacolgia tem vindo a desenvolver novos fármacos, por exemplo, compostos caged nos quais a sua atividade pode ser controlada de uma forma espácio-temporal através do uso de uma fonte de luz. MRS7145 (caged-SCH442416) foi o primeiro antagonista caged dos recetores A2A a ser sintetizado. Quando irradiado (405 nm), através de uma fonte externa de luz, este composto exibiu um perfil de antagonista relativamente aos recetores A2A em células vivas. No modelo de murganho da DP, induzido pela injeção de 6 hidroxidopamina (6-OHDA), demonstrou melhorias dos sintomas motores causados por esta doença. No entanto, a aplicação deste método envolve uma cirurgia ao cérebro complicada e requer o implante de fibras óticas, o que pode limitar a sua utilidade. O objetivo da presente tese foi avaliar se a bioluminescência gerada pela oxidação de coelenterazina 400a, através da enzima nanoluciferase (NL) acoplada ao recetor A2A (A2ARNL), seria suficiente para efetuar a libertação (uncaging) do composto MRS7145 em células vivas. Inicialmente, foi criada uma linha celular estável de células HEK-293 expressando permanentemente A2ARNL. Foram detetados baixos níveis de expressão deste recetor na membrana de células pertencentes à linha celular estável, comparativamente aos níveis detetados em células transientemente transfectadas com o mesmo vetor. Todavia, os valores acumulados de monofosfato cíclico de adenosina (cAMP) e alterações em impedância celular obtidos, após incubação com forskolina (ativador da adenilato ciclase), CGS21680 (agonista) e ZM241385 (antagonista), asseguraram a funcionalidade do recetor na linha celular criada. Além disso, 15 minutos de incubação com coelenterazina 400a, ou com o seu solvente, etanol, não provocou qualquer diminuição na viabilidade celular. No entanto, incubação com coelenterazina 400a levou à diminuição dos níveis de cAMP produzidos pela ação do agonista CGS21680, alterando as condições da ativação do recetor. Coelenterazina 400a não teve qualquer efeito na atividade do composto SCH442416 em bloquear o recetor A2A. Por fim, foi avaliado o bloqueio autónomo do recetor A2A mediado pela libertação (uncaging) do composto MRS7145 dependente da bioluminescência gerada pela enzima nanoluciferase acoplada. Quando incubado com coelenterazina 400a, o composto MRS7145 impediu a ativação do recetor de A2A mediada pelo agonista CGS21680. Resumindo, o método descrito baseado em bioluminescência, demonstrou a primeira evidência do uncaging do composto MRS7145 e subsequente libertação do composto SCH442416 em células vivas, sob um controlo espácio-temporal e independente de uma fonte externa de luz. Este método apresenta grande potencial para ser futuramente otimizado e aplicado no tratamento de distúrbios motores, incluindo a doença de Parkinson e, ainda, em terapias que visem a utilização de fármacos cuja atividade possa ser controlada por uma fonte de luz.
G protein-coupled receptors are key therapeutic targets for many pathological conditions. Studies support that the G protein-coupled adenosine A2A receptor (A2AR) and dopamine D2 receptor (D2R) form A2AR‐D2R heteromers in the striatum. The stoichiometry of this receptor heteromer is altered in Parkinson’s disease (PD) and A2AR signaling may be promoted. Hence, the A2AR represents the latest pharmacological target in PD. However, owing to the ubiquity of this receptor, it has been difficult to achieve drug selectivity in time and space for adenosine-based drugs which diminishes their therapeutic use. Photopharmacology has been developing novel drugs, e.g., caged-compounds, whose activity can be controlled in a spatiotemporal-manner with the use of a light source. MRS7145 (caged-SCH442416) was the first A2AR photo-caged antagonist to be synthesized whose external irradiation (405 nm) showed a light-dependent A2AR antagonist activity in living cells and antiparkinsonian effects in a hemiparkinsonian 6-hyroxydopamine (6-OHDA)-lesioned mouse model. However, this approach involves laborious brain surgery and optic fiber implants that may limit its utility. The aim of the present thesis was to evaluate whether the bioluminescence produced by an A2AR-coupled nanoluciferase (NL)-mediated coelenterazine 400a oxidation would be able to uncage MRS7145 in living cells. To begin with, a HEK-293 stable cell line expressing a previously engineered A2ARNL was created. Low receptor expression levels were found at the membrane of cells belonging to the stable cell line when compared to transiently transfected cells with the same construct. However, the cAMP accumulated levels and changes in cellular impedance obtained upon cell incubation with forskolin (adenylyl cyclase stimulator), CGS21680 (agonist), and ZM241385 (antagonist), ensured receptor functionality. Moreover, 15 minutes incubation with coelenterazine 400a or its solvent, ethanol, had no effect in decreasing cell viability, while incubation with coelenterazine 400a decreased CGS21680-induced cAMP accumulation altering receptor activation in the generated stable cell line. Coelenterazine 400a incubation did not affect SCH442416-induced receptor blockade. Finally, the autaptic A2AR blockade mediated by receptor’s bioluminescence-dependent uncaging of MRS7145 was evaluated. MRS7145 precluded CGS21680-induced receptor activation when incubated with coelenterazine 400a in living cells. Altogether, the described bioluminescence-based method provided the first proof of concept in uncaging MRS7145 and subsequent photorelease of SCH442416 in living cells, under a spatiotemporal control and independently of an external light source. This method demonstrates potential to be further optimized to be applied in the management of movement disorders, including Parkinson’s disease, and other prospective smart therapies which aim to utilize photocontrolled drugs.
Outro - SAF2017‐87349‐R from Ministerio de Economía y Competitividad‐Spanish Government, I+D (Project title: “Lighthing up dopamine, adenosine and GPR37 receptors in neurological and neuropsychiatric diseases”).

The concept of light-activated "caged" metal ions was first introduced for Ca2+. These high affinity coordination complexes are activated by UV light to release calcium ions intracellularly and have found widespread use in understanding the many roles of calcium in biological processes. There is an unmet need for photocaging ligands for biologically relevant transition metal ions. Described here are the first examples of uncaging biologically important d-block metal ions using photoactive ligands.

New nitrogen-donor ligands that contain a photoactive nitrophenyl group within the backbone have been prepared and evaluated for their metal binding affinity. Exposure of buffered aqueous solutions of apo-cage or metal-bound cage to UV light induces cleavage of the ligand backbone reducing the denticity of the ligands. Characterization of several caging compounds reveals that quantum efficiency and metal binding affinity can be tuned by modifications to the parent structure. The change in reactivity of caged vs. uncaged metal for promoting hydroxyl radical formation was demonstrated using the in vitro deoxyribose assay. The function of several of these compounds in vivo pre- and post-photolysis has been validated using MCF-7 cells. This strategy of caging transition metals ions is promising for applications where light can trigger the release of metal ions intracellularly to study metal trafficking and distribution, as well as, selectively impose oxidative stress and/or metal toxicity on malignant cells causing their demise.

Dissertation

碩士
國立臺灣大學
化學研究所
104
In supramolecular chemistry, constructing a well-defined three-dimensional cage has attracted more and more attention. Herein, we explore the possibility of exterior functionalization for the self-assembled cages. A series of tritopic terpyridine-based ligands with various exterior functionalities was used to construct metallo-supramolecular cages. To investigate the self-assembly behavior of the predesigned tritopic ligand system, ligands with simple hydroxyl and alkyl substituents were synthesized and complexed with Cd(II) and Zn(II) ions to give supramolecular cubic cages that were well characterized by 1H-NMR, ESI-MS, and electron microscopes. Besides, changing connected positions between the terpyridine moieties and the central core to generate a bent version of the tritopic ligand was successfully used for constructing a smaller supramolecular structure, demonstrating a simple method to build variant metallo-supramolecular structures. To date, the polymer solar cells (PSCs) with P3HT and PCBM as an active layer suffer from a severe lifetime problem, which is partly caused by the macrophase separation from the aggregation of PCBM with time. Based on our new findings, the tritopic terpyridine-based ligand decorated with pendant fullerene groups was successfully synthesized and self-assembled into a functional metallocage via coordination. In addition, the fullerene-functionalized cage was used as a supramolecular crosslinker to alleviate the macrophase aggregation caused by the migration of the C60 acceptor, which significantly improved the stability of organic photovoltaics.

碩士
國立臺灣大學
化學研究所
104
Molecular self-assembly using metal-ligand coordinative interaction has drawn much attention in recent years. Utilizing non-covalent interactions provides a facile way to construct large and complicated 2D/3D structures in contrast with the conventional organic chemistry. Moreover, incorporation of orthogonal host-guest and metal-coordination interactions into supramolecular structures will enhance their structural complexity and impart additional functions. In this research, we designed and synthesized a series of metallo-supramolecular cages possessing multiple (tpy = terpyridine) connections and ion–dipole interaction sites (i.e., crown ethers), which functioned orthogonally to each other. It was found that a decrease in the size of crown ethers leaded to a decrease in the flexibility, and thus various thermodynamic products were formed. To further study these metallo-supramolecular cages, we investigated the interactions between the crown ethers and the predesigned secondary ammonium ions. The 1:1 inclusion complex formed by the cage assembly and the multivalent ammonium salt was successfully achieved in MeCN and further characterized by NMR spectroscopy and ESI mass spectrometry. The formation of a metallo-supramolecular rotaxane based on the inclusion compound was explored as well.

In summary the present thesis accounts for the design and synthesis of various coordination cages formed through the self-assembly reaction of the newly designed pyridine and pyrimidine based ligands with various 90° palladium (II) and platinum (II) metal acceptors

Over the past few decades, supramolecular self-assembly has become an alternative synthetic tool for constructing targeted discrete molecular architectures. Among various interactions, metal-ligand coordination has attracted great attention owing to high bond enthalpy (15−50 Kcal/mol) and predictable directionality. The basic principle of metal-ligand directed self-assembly relies on the proper designing of information encoded rigid complementary building units (a transition metal based acceptor and a multidentate organic donor) that self-recognize themselves in a chemically reasonable way (depends on their bite angle and symmetry) during self-assembly process. As far as acceptor units are concerned, Pd(II) and Pt(II) metal-based cis-blocked 90° acceptors have so far been used greatly for the construction of a library of 2D/3D discrete supramolecular architectures due to their rigid square planar geometry and kinetic lability. However, in some cases the efforts to design finite supramolecular architectures using a cis-blocked 90° acceptor in combination with a bulky donor ligand were unsuccessful, which may be due to the steric demands of donor ligand. Moreover, the resulted assemblies from such cis-blocked 90° building unit are mostly non-fluorescent in nature and limit the possibility of using them as chemosensors for various practical applications. Unlike that of rigid square-planar Pt(II) and Pd(II)-metal based building blocks, the use of other transition metal-based building units for the construction of discrete nanoscopic molecular architectures are known to lesser extent, mainly because of their versatile coordination geometries. However, some of the half-sandwiched piano-stool complexes of late transition metals like Ru, Os, Ir and Rh are known to maintain the stable octahedral geometry under various reaction conditions. Moreover, the self-assembly using redox active transition metal-based building units may lead to redox active assemblies. On the other hand, symmetrical rigid donors have been widely used as the favorite choices for the purpose of constructing desired product mainly due to their predictable directionality. Flexible linkers are not predictable in their directionality during self-assembly process and thus results mostly in undesired polymeric products. Furthermore, metal-ligand directed self-assembly provides opportunity to introduce multifunctionality in a single step within/onto the final supramolecular architectures. Among various functional groups, the incorporation of unsaturated ethynyl functionality is expected to enrich the final assemblies to be π-electron-rich and the attachment of ethynyl functionality with heavy transition metal ions are known to be luminescent in nature due to the facile metal to ligand charge transfer (MLCT). Hence, the final supramolecular complexes can be used as potential fluorescence sensors for electron-deficient nitroaromatics, which are the chemical signature of most of the commercially available explosives. The main thrust of the present investigation is focused on the judicious design and syntheses of multifaceted 2D/3D supramolecular architectures of finite shapes, sizes and functionality using Pt(II)/Ru(II) based “shape-selective” organometallic building blocks and investigation of their application as chemosensors. CHAPTER 1 of the thesis presents a general review on the core concepts of self-assembly and supramolecular chemistry. In particular, it underlines the importance of metal-ligand directional bonding approach for designing a vast plethora of discrete 2D/3D supramolecular architectures with tremendous variation in topology. CHAPTER 2 describes the design and syntheses of a series of 2D metallamacrocycles using carbazole-functionalized shape-selective 90° building units. A new Pt2II organometallic 90° acceptor 3,6-bis[trans-Pt(PEt3)2(NO3)(ethynyl)]carbazole (M1) containing ethynyl functionality is synthesized via Sonagashira coupling reaction and characterized. The combination of M1 with three different flexible ditopic donors (L1−L3) afforded [2 + 2] self-assembled molecular squares (1−3), respectively [where L1 = 1,3-bis(4-pyridyl)isophthalamide; L2 = 1,3-bis(3-pyridyl)isophthalamide; L3 = 1,2-bis(4-pyridyl)ethane] (Scheme 1). Scheme 1: Schematic presentation of the formation of a series of [2 + 2] self-assembled molecular squares. An equimolar (1:1) combination of same acceptor M1 with rigid linear ditopic donors (L4-L5) yielded [4 + 4] self-assembled octanuclear molecular squares 4 and 5, respectively [L4 = 4,4’-bipyridine; L5 = trans-1,2-bis(4-pyridyl)ethylene]. Conversely, a similar reaction of M1 with an amide-based unsymmetrical linear flexible ditopic donor L6 resulted in the formation a [2 + 2] self-sorted molecular rhomboid (6a) as a single product [L6 = N-(4-pyridyl)isonicotinamide]. Despite the possibility of several linkage isomeric macrocycles (rhomboids, triangles and squares) due to different connectivity of the ambidentate linker, the formation of a single and symmetrical molecular rhomboid 6a as an exclusive product is an interesting observation. This chapter also presents the synthesis and characterization of a complementary 90° dipyridyl donor 3,6-bis(4-pyridylethynyl)carbazole (L7). Stoichiometric combination of L7 with several PdII/PtII-based 90° acceptors (M2−M4) yielded [2 + 2] self-assembled molecular “bowl” shaped macrocycles (7−9) respectively, in good yields [M2 = cis-(dppf)Pd(CF3SO3)2; M3 = cis-(dppf)Pt(CF3SO3)2; M4 = cis-(tmen)Pd(NO3)2]. All these newly synthesized macrocycles were characterized by various spectroscopic techniques and molecular structures of some of them were confirmed by single crystal X-ray diffraction analysis. In addition to their syntheses and characterization, fluorescence chemosensing ability for various analytes was investigated. Macrocycle 1 is a system composed of amide-based receptor units and carbazole-based fluorophore moieties. The fluorescence study of 1 elicited a dramatic enhancement in the fluorescence intensity upon gradual addition of P2O74- anion in DMF/H2O solvent mixture, whereas similar titration under identical condition with other anions like F-, ClO4-, and H2PO4- did not show such change. Hence, molecular square 1 can be used as selective fluorescence sensor for pyrophosphate (P2O74-) anion. Due to their extended π-conjugation, macrocycles 3-4 were used as fluorescence sensors for electron-deficient nitroaromatics, which are the chemical signatures of many commercially available explosives. The fluorescence study showed a marked quenching of initial fluorescence intensity of the macrocycles(3-4) upon gradual addition of picric acid (PA) and they exhibited large fluorescence quenching responses with high selectivity for nitroaromatics among various other electron deficient aromatic compounds tested. As macrocycle 7 has large concave aromatic surface, it was utilized as a suitable host for large convex guest such as fullerene C60. The fluorescence quenching titration study suggested that macrocycle 7 forms a stable ~1:1 host-guest complex with C60 and the calculated association constant (KSV) is 1.0 × 105 M-1. CHAPTER 3 presents two-component coordination-driven self-assembly of a series of [2 + 2] molecular rectangles and a [2 + 4] self-assembled molecular tetragonal prism. An equimolar combination of pre-designed linear PtII2-acceptors M5−M6 separately with three different “clip” donors (L2, L8−L9) led to the formation of [2 + 2] self-assembled tetranuclear cationic molecular rectangles (10−15), respectively [M5 = 1,4-bis[trans-Pt(PEt3)2(NO3)(ethynyl)] benzene; M6 = 4,4’-bis[trans-Pt(PEt3)2(CF3SO3)(ethynyl)]biphenyl; L8 = 1,3-bis(3-pyridyl)ethynylbenzene; L9 = 1,8-bis(4-pyridyl)ethynylanthracene]. Rectangles 10-15 showed strong fluorescence in solution owing to their extended π-conjugation. Amide-functionalized rectangle 10 was used as a macrocyclic receptor for dicarboxylic acids. Solution state fluorescence study showed that rectangle 10 selectively binds (KSV = 1.4 × 104 M-1) with maleic acid by subsequent enhancement in emission intensity and addition of other analogous aliphatic dicarboxylic acids such as fumaric, succinic, adipic, mesaconic and itaconic acids causes no change in the emission spectra; thereby demonstrated its potential use as macrocyclic receptor in sensor applications. Since rectangle 15 is enriched with π-conjugation, it was examined as a fluorescence sensor for electron-deficient nitroaromatics such as picric acid, which is often considered as a secondary chemical explosive. The fluorescence study of 15 showed a significant quenching of initial emission intensity upon titrating with picric acid (PA) and it exhibited the largest fluorescence quenching response with high selectivity for picric acid. Scheme 2: Schematic representation of formation of [2 + 4] self-assembled of molecular tetragonal prism. This chapter also describes two-component coordination [2 + 4] self-assembly of a pyrene-based PtII8 tetragonal prism (16) as shown in Scheme 2, using a newly designed tetratopic organometallic acceptor (M7; 1,3,6,8-tetrakis[trans-Pt(PEt3)2(NO3)(ethynyl)]pyrene) in combination with an amide-based “clip” donor (L2) and propensity of this prism (16) as a selective fluorescence sensor for nitroaromatic explosives has been examined both in solution as well as in thin-film. CHAPTER 4 reports the synthesis and structural characterization of a series of Ru(II)-based bi-and tetra-nuclear metallamacrocycles and hexanuclear trigonal prismatic cages. In principle, the self-assembly of a “clip” acceptor with an asymmetrical ditopic donor is expected to give two different linkage isomeric (head-to-tail and head-to-head) molecular rectangles because of different bond connectivity of the donor. However, the equimolar combination of half-sandwiched p-cymene binuclear Ru(II)-based “clip” acceptors (M8−M9) and an amide-based ambidentate donor (L6) resulted in the self-sorting of single linkage (head-to-tail) isomeric rectangles 17−18 as only products, respectively [M8 = [Ru2(μ-η4-C2O4)(MeOH)2(η 6-p-cymene)2](CF3SO3)2; M9 = [Ru2(μ- η4-C6H2O4)(MeOH)2(η 6-p-cymene)2](CF3SO3)2]. Molecular structures of these head-to-tail linkage isomeric rectangles were unambiguously proved by single crystal X-ray diffraction analysis. Likewise, the self-assembly of oxalato-bridged Ru(II) acceptor M8 with a rigid dipyridyl “clip” donor L8 yielded a tetranuclear cationic pincer complex 19, while a similar reaction of M8 with an anthracene-functionalized “clip” donor L9 having shorter distance (between their reactive sites) compared to L8 led to the formation of [1 + 1] self-assembled macrocycle 20. This chapter also represents the design and synthesis of two hexanuclear trigonal prismatic cages (21−22) from the self-assembly of a π-electron rich tripyridyl donor (L10; 1,3,5-tris(4-pyridylethynyl)benzene) in combination with binuclear acceptors M8 and M9, respectively (Scheme 3). Formation of these prismatic cages was initially characterized using various spectroscopic techniques and the molecular structure of oxalato-bridged prism 21 was confirmed by single crystal X-ray diffraction analysis. In addition to the structural characterization, the pincer complex 19 and trigonal prismatic cages 21−22 were used as fluorescence sensors for nitroaromatic explosives owing to their large internal porosity and their π-electron rich nature. Scheme 3: Schematic representation of the formation of [3 + 2] self-assembled trigonal prismatic cage. CHAPTER 5 covers the syntheses of a few discrete metallamacrocycles using flexible imidazole/carboxylate based donors instead of much widely employed polypyridyl donors. The metal-ligand directed self-assembly of oxalato-bridged acceptor M8 and an imidazole-based tetratopic donor (L11; 1,2,4,5-tetrakis(imidazol-1-yl)benzene) in methanol afforded [2 + 1] self-assembled tetranuclear macrocycle 23. Conversely, the similar combination of L11 with 2,5-dihydroxy-1,4-benzoquinonato-bridged binuclear complex (M9) in 1:2 molar ratio in methanol resulted in an octanuclear cage 24. Both the complexes (23−24) were isolated as their triflate salts in high yields and were characterized by various spectroscopic methods including single crystal X-ray diffraction analysis. Scheme 4: Schematic representation of formation of an octanuclear incomplete Ru(II) open prism via ruthenium-oxygen coordination driven self-assembly. This chapter also explains the self-sorting of an unusual octanuclear incomplete prism [Ru8(η6-p-cymene)8(tma)2(μ-η4-C2O4)2(OMe)4](CF3SO3)2 (25) via ruthenium-oxygen coordination driven self-assembly of building block M8 and sodium benzene-1,3,5-tricarboxylate (L12) (Scheme 4). Electronic absorption study indicated that prism 25 exhibited a remarkable shape-selective binding affinity for 1,3,5-trihydroxybenzene (phluoroglucinol) via multiple hydrogen bonding interactions and such shape-selective binding was confirmed by single crystal X-ray diffraction analysis. (For figures pl see the abstract file)

Over the past few decades, supramolecular self-assembly has become an alternative synthetic tool for constructing targeted discrete molecular architectures. Among various interactions, metal-ligand coordination has attracted great attention owing to high bond enthalpy (15−50 Kcal/mol) and predictable directionality. The basic principle of metal-ligand directed self-assembly relies on the proper designing of information encoded rigid complementary building units (a transition metal based acceptor and a multidentate organic donor) that self-recognize themselves in a chemically reasonable way (depends on their bite angle and symmetry) during self-assembly process. As far as acceptor units are concerned, Pd(II) and Pt(II) metal-based cis-blocked 90° acceptors have so far been used greatly for the construction of a library of 2D/3D discrete supramolecular architectures due to their rigid square planar geometry and kinetic lability. However, in some cases the efforts to design finite supramolecular architectures using a cis-blocked 90° acceptor in combination with a bulky donor ligand were unsuccessful, which may be due to the steric demands of donor ligand. Moreover, the resulted assemblies from such cis-blocked 90° building unit are mostly non-fluorescent in nature and limit the possibility of using them as chemosensors for various practical applications. Unlike that of rigid square-planar Pt(II) and Pd(II)-metal based building blocks, the use of other transition metal-based building units for the construction of discrete nanoscopic molecular architectures are known to lesser extent, mainly because of their versatile coordination geometries. However, some of the half-sandwiched piano-stool complexes of late transition metals like Ru, Os, Ir and Rh are known to maintain the stable octahedral geometry under various reaction conditions. Moreover, the self-assembly using redox active transition metal-based building units may lead to redox active assemblies. On the other hand, symmetrical rigid donors have been widely used as the favorite choices for the purpose of constructing desired product mainly due to their predictable directionality. Flexible linkers are not predictable in their directionality during self-assembly process and thus results mostly in undesired polymeric products. Furthermore, metal-ligand directed self-assembly provides opportunity to introduce multifunctionality in a single step within/onto the final supramolecular architectures. Among various functional groups, the incorporation of unsaturated ethynyl functionality is expected to enrich the final assemblies to be π-electron-rich and the attachment of ethynyl functionality with heavy transition metal ions are known to be luminescent in nature due to the facile metal to ligand charge transfer (MLCT). Hence, the final supramolecular complexes can be used as potential fluorescence sensors for electron-deficient nitroaromatics, which are the chemical signature of most of the commercially available explosives. The main thrust of the present investigation is focused on the judicious design and syntheses of multifaceted 2D/3D supramolecular architectures of finite shapes, sizes and functionality using Pt(II)/Ru(II) based “shape-selective” organometallic building blocks and investigation of their application as chemosensors. CHAPTER 1 of the thesis presents a general review on the core concepts of self-assembly and supramolecular chemistry. In particular, it underlines the importance of metal-ligand directional bonding approach for designing a vast plethora of discrete 2D/3D supramolecular architectures with tremendous variation in topology. CHAPTER 2 describes the design and syntheses of a series of 2D metallamacrocycles using carbazole-functionalized shape-selective 90° building units. A new Pt2II organometallic 90° acceptor 3,6-bis[trans-Pt(PEt3)2(NO3)(ethynyl)]carbazole (M1) containing ethynyl functionality is synthesized via Sonagashira coupling reaction and characterized. The combination of M1 with three different flexible ditopic donors (L1−L3) afforded [2 + 2] self-assembled molecular squares (1−3), respectively [where L1 = 1,3-bis(4-pyridyl)isophthalamide; L2 = 1,3-bis(3-pyridyl)isophthalamide; L3 = 1,2-bis(4-pyridyl)ethane] (Scheme 1). Scheme 1: Schematic presentation of the formation of a series of [2 + 2] self-assembled molecular squares. An equimolar (1:1) combination of same acceptor M1 with rigid linear ditopic donors (L4-L5) yielded [4 + 4] self-assembled octanuclear molecular squares 4 and 5, respectively [L4 = 4,4’-bipyridine; L5 = trans-1,2-bis(4-pyridyl)ethylene]. Conversely, a similar reaction of M1 with an amide-based unsymmetrical linear flexible ditopic donor L6 resulted in the formation a [2 + 2] self-sorted molecular rhomboid (6a) as a single product [L6 = N-(4-pyridyl)isonicotinamide]. Despite the possibility of several linkage isomeric macrocycles (rhomboids, triangles and squares) due to different connectivity of the ambidentate linker, the formation of a single and symmetrical molecular rhomboid 6a as an exclusive product is an interesting observation. This chapter also presents the synthesis and characterization of a complementary 90° dipyridyl donor 3,6-bis(4-pyridylethynyl)carbazole (L7). Stoichiometric combination of L7 with several PdII/PtII-based 90° acceptors (M2−M4) yielded [2 + 2] self-assembled molecular “bowl” shaped macrocycles (7−9) respectively, in good yields [M2 = cis-(dppf)Pd(CF3SO3)2; M3 = cis-(dppf)Pt(CF3SO3)2; M4 = cis-(tmen)Pd(NO3)2]. All these newly synthesized macrocycles were characterized by various spectroscopic techniques and molecular structures of some of them were confirmed by single crystal X-ray diffraction analysis. In addition to their syntheses and characterization, fluorescence chemosensing ability for various analytes was investigated. Macrocycle 1 is a system composed of amide-based receptor units and carbazole-based fluorophore moieties. The fluorescence study of 1 elicited a dramatic enhancement in the fluorescence intensity upon gradual addition of P2O74- anion in DMF/H2O solvent mixture, whereas similar titration under identical condition with other anions like F-, ClO4-, and H2PO4- did not show such change. Hence, molecular square 1 can be used as selective fluorescence sensor for pyrophosphate (P2O74-) anion. Due to their extended π-conjugation, macrocycles 3-4 were used as fluorescence sensors for electron-deficient nitroaromatics, which are the chemical signatures of many commercially available explosives. The fluorescence study showed a marked quenching of initial fluorescence intensity of the macrocycles(3-4) upon gradual addition of picric acid (PA) and they exhibited large fluorescence quenching responses with high selectivity for nitroaromatics among various other electron deficient aromatic compounds tested. As macrocycle 7 has large concave aromatic surface, it was utilized as a suitable host for large convex guest such as fullerene C60. The fluorescence quenching titration study suggested that macrocycle 7 forms a stable ~1:1 host-guest complex with C60 and the calculated association constant (KSV) is 1.0 × 105 M-1. CHAPTER 3 presents two-component coordination-driven self-assembly of a series of [2 + 2] molecular rectangles and a [2 + 4] self-assembled molecular tetragonal prism. An equimolar combination of pre-designed linear PtII2-acceptors M5−M6 separately with three different “clip” donors (L2, L8−L9) led to the formation of [2 + 2] self-assembled tetranuclear cationic molecular rectangles (10−15), respectively [M5 = 1,4-bis[trans-Pt(PEt3)2(NO3)(ethynyl)] benzene; M6 = 4,4’-bis[trans-Pt(PEt3)2(CF3SO3)(ethynyl)]biphenyl; L8 = 1,3-bis(3-pyridyl)ethynylbenzene; L9 = 1,8-bis(4-pyridyl)ethynylanthracene]. Rectangles 10-15 showed strong fluorescence in solution owing to their extended π-conjugation. Amide-functionalized rectangle 10 was used as a macrocyclic receptor for dicarboxylic acids. Solution state fluorescence study showed that rectangle 10 selectively binds (KSV = 1.4 × 104 M-1) with maleic acid by subsequent enhancement in emission intensity and addition of other analogous aliphatic dicarboxylic acids such as fumaric, succinic, adipic, mesaconic and itaconic acids causes no change in the emission spectra; thereby demonstrated its potential use as macrocyclic receptor in sensor applications. Since rectangle 15 is enriched with π-conjugation, it was examined as a fluorescence sensor for electron-deficient nitroaromatics such as picric acid, which is often considered as a secondary chemical explosive. The fluorescence study of 15 showed a significant quenching of initial emission intensity upon titrating with picric acid (PA) and it exhibited the largest fluorescence quenching response with high selectivity for picric acid. Scheme 2: Schematic representation of formation of [2 + 4] self-assembled of molecular tetragonal prism. This chapter also describes two-component coordination [2 + 4] self-assembly of a pyrene-based PtII8 tetragonal prism (16) as shown in Scheme 2, using a newly designed tetratopic organometallic acceptor (M7; 1,3,6,8-tetrakis[trans-Pt(PEt3)2(NO3)(ethynyl)]pyrene) in combination with an amide-based “clip” donor (L2) and propensity of this prism (16) as a selective fluorescence sensor for nitroaromatic explosives has been examined both in solution as well as in thin-film. CHAPTER 4 reports the synthesis and structural characterization of a series of Ru(II)-based bi-and tetra-nuclear metallamacrocycles and hexanuclear trigonal prismatic cages. In principle, the self-assembly of a “clip” acceptor with an asymmetrical ditopic donor is expected to give two different linkage isomeric (head-to-tail and head-to-head) molecular rectangles because of different bond connectivity of the donor. However, the equimolar combination of half-sandwiched p-cymene binuclear Ru(II)-based “clip” acceptors (M8−M9) and an amide-based ambidentate donor (L6) resulted in the self-sorting of single linkage (head-to-tail) isomeric rectangles 17−18 as only products, respectively [M8 = [Ru2(μ-η4-C2O4)(MeOH)2(η 6-p-cymene)2](CF3SO3)2; M9 = [Ru2(μ- η4-C6H2O4)(MeOH)2(η 6-p-cymene)2](CF3SO3)2]. Molecular structures of these head-to-tail linkage isomeric rectangles were unambiguously proved by single crystal X-ray diffraction analysis. Likewise, the self-assembly of oxalato-bridged Ru(II) acceptor M8 with a rigid dipyridyl “clip” donor L8 yielded a tetranuclear cationic pincer complex 19, while a similar reaction of M8 with an anthracene-functionalized “clip” donor L9 having shorter distance (between their reactive sites) compared to L8 led to the formation of [1 + 1] self-assembled macrocycle 20. This chapter also represents the design and synthesis of two hexanuclear trigonal prismatic cages (21−22) from the self-assembly of a π-electron rich tripyridyl donor (L10; 1,3,5-tris(4-pyridylethynyl)benzene) in combination with binuclear acceptors M8 and M9, respectively (Scheme 3). Formation of these prismatic cages was initially characterized using various spectroscopic techniques and the molecular structure of oxalato-bridged prism 21 was confirmed by single crystal X-ray diffraction analysis. In addition to the structural characterization, the pincer complex 19 and trigonal prismatic cages 21−22 were used as fluorescence sensors for nitroaromatic explosives owing to their large internal porosity and their π-electron rich nature. Scheme 3: Schematic representation of the formation of [3 + 2] self-assembled trigonal prismatic cage. CHAPTER 5 covers the syntheses of a few discrete metallamacrocycles using flexible imidazole/carboxylate based donors instead of much widely employed polypyridyl donors. The metal-ligand directed self-assembly of oxalato-bridged acceptor M8 and an imidazole-based tetratopic donor (L11; 1,2,4,5-tetrakis(imidazol-1-yl)benzene) in methanol afforded [2 + 1] self-assembled tetranuclear macrocycle 23. Conversely, the similar combination of L11 with 2,5-dihydroxy-1,4-benzoquinonato-bridged binuclear complex (M9) in 1:2 molar ratio in methanol resulted in an octanuclear cage 24. Both the complexes (23−24) were isolated as their triflate salts in high yields and were characterized by various spectroscopic methods including single crystal X-ray diffraction analysis. Scheme 4: Schematic representation of formation of an octanuclear incomplete Ru(II) open prism via ruthenium-oxygen coordination driven self-assembly. This chapter also explains the self-sorting of an unusual octanuclear incomplete prism [Ru8(η6-p-cymene)8(tma)2(μ-η4-C2O4)2(OMe)4](CF3SO3)2 (25) via ruthenium-oxygen coordination driven self-assembly of building block M8 and sodium benzene-1,3,5-tricarboxylate (L12) (Scheme 4). Electronic absorption study indicated that prism 25 exhibited a remarkable shape-selective binding affinity for 1,3,5-trihydroxybenzene (phluoroglucinol) via multiple hydrogen bonding interactions and such shape-selective binding was confirmed by single crystal X-ray diffraction analysis. (For figures pl see the abstract file)

Coordination of transition metals to peptides, either through the incorporation of unnatural chelating groups or amino acid ligating side-chains, expands the utility of peptides for biological studies. The first part of this project describes induction of α-helical secondary structure in pentapeptides upon side-chain coordination of inert transition metal ions. The second part of this project describes the syntheses of biologically active peptide species that contain a macrobicyclic hexaamine ligand that can complex radioactive metal ions for diagnostic imaging purposes.
Short peptide sequences do not form thermodynamically stable α-helices in water. The capacity of two metal clips, cis-[Ru(NH3)4(solvent)2]2+ and cis [Pd(en)(solvent)2]2+ to induce α-helicity in peptides that are five amino acids long, Ac HARAH NH2 and Ac MARAM-NH2 has been explored. In all cases at pH < 5, the metal ions bind to the side-chains of amino acid residues at positions i, i+4 of the pentapeptides resulting in formation of bidentate macrocyclic species. Circular dichroism and 1H nuclear magnetic resonance data indicate that the metal complexes of Ac-MARAM-NH2 are highly α helical in water, and in the most spectacular case, coordination of Ac-MARAM-NH2 to cis-[Ru(NH3)4(solvent)2]2+ results in up to 80% α-helicity. In contrast, metal complexes of Ac-HARAH-NH2 exhibit significantly less α-helicity in water.
64Cu-radiolabelled peptides have been investigated for their ability to target specific tissue or cell types. These peptides require a chelating group that binds copper ions strongly. Macrobicyclic hexaamine ligands, based on the compound commonly referred to as “sarcophagine”, have demonstrated extremely high stability under biological conditions. Here we describe the synthesis of diaminosarcophagine chelators with carboxylate groups for conjugation to peptides. These new chelators have been attached to the N-terminus or lysine side-chain of biologically-active peptides, including Tyr3 octreotate, Lys3-bombesin and an integrin targeting peptide. Spectroscopic and voltammetric studies of these species suggest that the conjugated sarcophagine group retains the high metal binding affinity and structural properties of the parent species, diaminosarcophagine. These are among the first sarcophagine-peptide compounds that have been properly characterised. The new sarcophagine-peptide conjugates can be easily radiolabelled with 64Cu2+ over a wide pH range at ambient temperature.