Rozprawy doktorskie na temat „Copper-based complexes”

Aquesta Tesi Doctoral es centra en l’estudi de catalitzadors moleculars per a l’oxidació d’aigua basats en coure i níquel, ja que la seva gran abundància i baix cost els fa potencials candidats pel seu ús en sistemes catalítics. Tot i així, avui en dia hi ha una important mancança d’informació respecte als seus mecanismes de reacció i els factors que influeixen la seva activitat. Per això, en primer lloc, es desenvolupen nous catalitzadors moleculars basats en el coure com a centre metàl·lic. L’estudi mecanístic d’aquests catalitzadors revela l’important rol que té l’oxidació del lligand en el cicle catalític a l’hora de controlar el sobre-potencial de la reacció. Al mateix temps, en col·laboració amb el grup del Professor Maseras (ICIQ) es descobreix un nou mecanisme per a la formació de l’enllaç oxigen-oxigen que opera en diferents tipus catalitzadors de coure. Aquest nou mecanisme sense precedents permet redefinir l’escenari mecanístic per a l’oxidació d’aigua. Posteriorment, es realitza el disseny de nous lligands amb diferents propietats redox que permeten estudiar factors que influeixen en l’activitat i el mecanisme de reacció. Això proporciona informació rellevant per al disseny de nous catalitzadors més actius, estables i eficients. També s’aborda la immobilització dels catalitzadors desenvolupats sobre els elèctrodes basats en grafè. D’aquesta manera es descobreix el paper essencial que té la deslocalització d’electrons en els orbitals π, que permet incrementar la cinètica de la reacció per més de dues ordres de magnitud. Finalment, el coneixement generat en coure s’intenta expandir per a la seva aplicació en els catalitzadors de níquel. Això permet estudiar el caràcter làbil dels complexos de níquel en medis bàsics, que determina la presència de dos mecanismes d’operació basats en espècies moleculars i òxids de níquel respectivament.
Esta Tesis Doctoral se centra en el estudio de catalizadores moleculares para la oxidación de agua basados en cobre y níquel, ya que su gran abundancia y su bajo coste los hace potenciales candidatos para su uso en sistemas catalíticos. A pesar de esto, hoy en día hay una importante carencia de información con respecto a sus mecanismos de reacción y los factores que determinan su actividad. Por ello, en primer lugar, se desarrollan nuevos catalizadores moleculares basados en cobre como centro metálico. El estudio mecanístico de dichos catalizadores revela el importante rol que tiene la oxidación del ligando en el ciclo catalítico a la hora de controlar el sobre-potencial de la reacción. Al mismo tiempo, en colaboración con el grupo del Profesor Maseras (ICIQ) se descubre un nuevo mecanismo para la formación del enlace oxígeno-oxígeno que opera en diferentes tipos de catalizadores de cobre. Este nuevo mecanismo sin precedentes permite redefinir el escenario mecanístico para la oxidación de agua. Posteriormente, se realiza el diseño de nuevos ligandos con diferentes propiedades redox que permiten estudiar los factores que influyen en la actividad y el mecanismo de reacción. Esto proporciona información relevante para el diseño de nuevos catalizadores más activos, estables y eficientes. También se aborda la inmovilización de los catalizadores desarrollados sobre electrodos basados en grafeno. De esta forma se descubre el papel esencial que tiene la deslocalización de electrones en orbitales π, que permite incrementar la cinética de reacción por más de dos órdenes de magnitud. Finalmente, el conocimiento generado en cobre se intenta expandir para su aplicación en catalizadores de níquel. Esto permite estudiar el carácter lábil de los complejos de níquel en medios básicos, que determina la presencia de dos mecanismos de operación basados en especies moleculares y óxidos de níquel respectivamente.
This Doctoral Thesis focuses on the study of molecular catalysts for water oxidation based on copper and nickel since their high abundance and inexpensive character make them potential candidates for their use in catalytic systems. Despite that, there is a current lack of information regarding their reaction mechanism and the factors that determine their activity. Therefore, we first develop new molecular catalysts based on copper as metal center. Their mechanistic study reveals the essential role that the ligand oxidation has in the catalytic cycle as tool to control the reaction overpotential. In collaboration with Prof. Maseras group (ICIQ) a new mechanism for the oxygen-oxygen bond formation is found to operate in different copper catalysts. This unprecedented mechanism allows us to redefine the mechanistic scenario in water oxidation. Later on, the design of new ligands with different redox properties is addressed. That allows to study the factors that have influence on the activity and reaction mechanism and provide valuable information for the design of more active, stable and efficient new catalysts. Moreover, the immobilization of the molecular catalyst on the surface of graphene-based electrodes is also studied. We discover the essential role of the π-delocalization in increasing the reaction kinetic by more than two orders of magnitude. Finally, the knowledge developed with copper complexes is applied in nickel catalysis. This allows to study the labile character of nickel complexes in basic media that determine the presence of two different operating mechanism based on molecular species and nickel oxides respectively.

The research reported in this thesis was carried out in Brisbane, Australia and Calgary, Canada. The aim of the research conducted in Brisbane was to prepare a series of copper(I) and ruthenium(II) based complexes incorporating a hemilabile phosphine ligand and to determine whether or not these compounds possessed catalytic activity. The history, uses, properties and recent work incorporating hemilabile phosphine ligands is discussed in detail as well as the application of hemilabile ligands to atom transfer radical polymerization (ATRP) and the usefulness of the 'windscreen wiper' action of these ligands in polymerization. The literature synthesis and characterization of four hemilabile phosphine ligands is reported with modifications. The (2-chlorophenyl)diphenylphosphine ligand was prepared via a Grignard reaction giving a 11% yield. The (2-bromophenyl) diphenylphosphine ligand was prepared by reaction of 2-bromoiodobenzene with Ph2PSiMe3 in the presence of a palladium catalyst (MeCN)2PdCl2 which yielded 50% product. The 1-chloro-2-diphenylphosphinoethane ligand was prepared following the generation of a lithium diphenylphosphide which was added to 1,2-dichloroethane to give a 43% yield of product. The (2-benzoic-acid)diphenylphosphine ligand was prepared by hydrolysis of (2-methyl-ester-phenyl)diphenylphosphine. Following acidification of the methyl ester phosphine with HCl, the desired product was isolated in 88% yield. The synthesis and characterization of a series of copper(I) based complexes incorporating the prepared phosphine ligands involved reaction in CH3CN of the appropriate ligand with copper halides as starting material. Solution state 31P NMR and mass spectrometry were used to study many of these complexes in the solution state, whilst microanalysis, 31P CP MAS NMR and single crystal X-ray diffraction studies were used to study their solid state properties. The complexes of the type bis(2-halophenyl)diphenylphosphine copper halide were found to be three coordinate with non-chelating ligands and to be isostructural with the previously studied bis(2-methylphenyl)diphenylphosphine copper halide complexes. The synthesis and characterization of ruthenium(II) based complexes incorporating hemilabile phosphine ligands involved reaction of the appropriate ligands in MeOH with RuCl3.3H2O or RuCl2(DMSO)4 as the ruthenium source. Modes of characterization included solution state 31P NMR, mass spectrometry, microanalysis and single crystal X-ray diffraction studies. All ruthenium(II) based complexes were found to incorporate the hemilabile ligands in a chelating mode resulting in 6 coordinate structures. The preliminary polymerization testing of MMA in the presence of the copper(I) and ruthenium(II) based complexes has been reported. All complexes successfully polymerized the monomer and the resulting polyMMA showed polydispersity values ranging from moderate (3.1) to very high (6.7). Chapter 7 discusses research conducted over a 6 month period at the University of Calgary, Canada under an International Resident Fellowship award. This work involved the synthesis and characterization of scandium(III) and yttrium(III) based complexes incorporating a chelating amido-imine ligand, as potential olefin polymerization catalysts.

The research reported in this thesis was carried out in Brisbane, Australia and Calgary, Canada. The aim of the research conducted in Brisbane was to prepare a series of copper(I) and ruthenium(II) based complexes incorporating a hemilabile phosphine ligand and to determine whether or not these compounds possessed catalytic activity. The history, uses, properties and recent work incorporating hemilabile phosphine ligands is discussed in detail as well as the application of hemilabile ligands to atom transfer radical polymerization (ATRP) and the usefulness of the 'windscreen wiper' action of these ligands in polymerization. The literature synthesis and characterization of four hemilabile phosphine ligands is reported with modifications. The (2-chlorophenyl)diphenylphosphine ligand was prepared via a Grignard reaction giving a 11% yield. The (2-bromophenyl) diphenylphosphine ligand was prepared by reaction of 2-bromoiodobenzene with Ph2PSiMe3 in the presence of a palladium catalyst (MeCN)2PdCl2 which yielded 50% product. The 1-chloro-2-diphenylphosphinoethane ligand was prepared following the generation of a lithium diphenylphosphide which was added to 1,2-dichloroethane to give a 43% yield of product. The (2-benzoic-acid)diphenylphosphine ligand was prepared by hydrolysis of (2-methyl-ester-phenyl)diphenylphosphine. Following acidification of the methyl ester phosphine with HCl, the desired product was isolated in 88% yield. The synthesis and characterization of a series of copper(I) based complexes incorporating the prepared phosphine ligands involved reaction in CH3CN of the appropriate ligand with copper halides as starting material. Solution state 31P NMR and mass spectrometry were used to study many of these complexes in the solution state, whilst microanalysis, 31P CP MAS NMR and single crystal X-ray diffraction studies were used to study their solid state properties. The complexes of the type bis(2-halophenyl)diphenylphosphine copper halide were found to be three coordinate with non-chelating ligands and to be isostructural with the previously studied bis(2-methylphenyl)diphenylphosphine copper halide complexes. The synthesis and characterization of ruthenium(II) based complexes incorporating hemilabile phosphine ligands involved reaction of the appropriate ligands in MeOH with RuCl3.3H2O or RuCl2(DMSO)4 as the ruthenium source. Modes of characterization included solution state 31P NMR, mass spectrometry, microanalysis and single crystal X-ray diffraction studies. All ruthenium(II) based complexes were found to incorporate the hemilabile ligands in a chelating mode resulting in 6 coordinate structures. The preliminary polymerization testing of MMA in the presence of the copper(I) and ruthenium(II) based complexes has been reported. All complexes successfully polymerized the monomer and the resulting polyMMA showed polydispersity values ranging from moderate (3.1) to very high (6.7). Chapter 7 discusses research conducted over a 6 month period at the University of Calgary, Canada under an International Resident Fellowship award. This work involved the synthesis and characterization of scandium(III) and yttrium(III) based complexes incorporating a chelating amido-imine ligand, as potential olefin polymerization catalysts.
Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Science
Faculty of Science
Full Text

Thesis (MSc (Chemistry and Polymer Science))--University of Stellenbosch, 2010.
ENGLISH ABSTRACT: In this thesis we describe the synthesis of several new N-(n-propyl)-1-(2-pyridyl and quinolyl)-imine ligands (ML1-ML4) as well as peripheral functionalised iminopyridyl and iminoquinolyl poly(propylene-imine) dendrimeric ligands (DL1-DL8) with a 1,4- diaminobutane core. The dendrimeric ligands were obtained by modification of the peripheral groups of Generation 1 and Generation 2 poly(propylene-imine) dendrimers, (DAB-(NH2)n which are commercially available, with a series of aldehydes. All the ligands were fully characterised by ESI-mass spectrometry, elemental analysis, 1H&13C{1H}-NMR, FT-IR and UV/Vis spectroscopies. These ligands were utilised to synthesise Pd(II) and Cu(I) complexes using appropriate metal precursors. Some of mononuclear complexes, [N-(n-propyl)-(2-pyridyl and quinolyl) methanimine] dichloro Pd(II) complexes (C1-C4) and bis[N-(n-propyl)-(2-pyridyl and quinolyl) methanimine] copper(I) tetrafluoroborate complexes (C14) were structurally characterised. Pd(II) complexes adopted a distorted square-planar geometry around the metal centre while Cu(I) complex exhibit a distorted tetrahedral arrangement around the metal centre. Both Pd(II) and Cu(I) multinuclear complexes (metallodendrimers) were characterised using a range of analytical techniques.
AFRIKAANSE OPSOMMING: In hierdie tesis word die sintese van verskeie nuwe N-(n-propiel)-1-(2-piridiel) en kinolielimien ligande (ML1-ML4) sowel as gefunksioneerde imienopiridiel en imienokinoliel poli(propilien-imien) dendrimeriese ligande (DL1-DL8) beskryf. Die dendrimeriese ligande was behaal deur die modifikasie van perifere groepe van Generasie 1 en Generasie 2 poli(propilien-imien) dendrimere met ‘n reeks aldehiede. Alle ligande was volledig deur ESI-massaspektrometrie, elementele analiese, 1H en 13C{1H} – KMR, FT-IR en UV/Sigbare spektroskopie gekarakteriseerd. Hierdie ligande was gebruik om Pd(II) en Cu(I) komplekse te berei om van die gepaste metaal voorlopers te gebruik te maak. Sommige van die mono-kern komplekse, [N-(npropiel)-( 2-piridiel) en kinoliel metanimien] dikloor Pd(II), komplekse (C1-C4) en bis[N-(npropiel)-( 2-piridiel) metanimien] koper(I) tetrafloorboraat, kompleks (C14) was struktureël gekarakteriseerd. Pd(II) komplekse neem ‘n versteurde vierkant valk geometrie om die metaal senter aan, terwyl die Cu(I) kompleks, ‘n versteurde tetrahedriese opset rondom die metaal toon. Beide Pd(II) en Cu(I) multikern komplekse (metaaldendrimere) was deur ‘n verskeidenheid van analitiese tegnieke gekarakteriseerd.

Several Schiff base ligands, N, N‟-(aryl)benzyaldiimine ligands (R-BEN); N, N‟-(aryl)benzyaldiamine dihydrochloride ligands (R-BENH•2HCl); N, N‟-(aryl)benzyaldiamine ligands (R-BENH); N, N‟-bis(cinnamaldiimine) ligands (R-CA2EN) were synthesized for the investigation of the electronic effect of the substituents at para-position of the Schiff base ligands and their copper complexes. The synthesis of Schiff bases was carried out by reacting a series of para-substituted benzyaldehyde, and para-substituted cinnamaldehyde with ethylenediamine. The imine group of Schiff bases, N, N‟-(aryl)benzyaldiimine ligands and N, N‟-bis(cinnamaldiimine)ligands were reduced to corresponding amines with sodium borohydride in methanol These ligands, N, N‟-(aryl)benzyaldiamine ligands (H-BENH), N, N‟-bis(cinnamaldiimine)ligands (CA2EN) were reacted with copper(II) dihalide and copper(I) monohalide ions respectively to form complexes. The ligands and their complexes were analysed using elemental analyses, FT-IR spectroscopy (mid-IR), UV/vis in aprotic and protic solvents,while mass spectrometry, 1H-NMR and 13C-NMR were used to further analyse the ligands. By using substituent parameters, both the single and dual substituent parameters with the spectroscopic data obtained from the spectroscopic techiques mentioned above, it was hoped to monitor and determine whether the electronic effects (resonance or inductive effcets) was predominantly within the Schiff base ligands and copper complexes. The NMR studies with dual substituent parameters suggest that the effects of the substituents are transimitted through the ligands, via resonance effects and that the phenyl group is nonplanar with the azomethine in N, N‟-(aryl)benzyaldiimine ligands. The presence of an extra double bond in Schiff base {(N, N‟-bis(cinnamaldiimine) ligand)} altered the electron density. The UV/vis studies showed that the symmetry of the N, N‟-bis(4-R-benzyl)-1, 2-diaminoethanedihalidecopper(II) complexes were predominantly tetrahedral for both chloro and bromo complexes. The correlation studies from mid-infrared were beneficial in monitoring the effect experienced by N, N‟-(aryl)benzaldiimine ligands, the studies suggest that the inductive effect is more pronounced at the C=N.

Thesis advisor: Amir H. Hoveyda
Chapter 1 Enantioselective Conjugate Additions of Carbon Nucleophiles to Activated Olefins: Preparation of Enantioenriched Compounds Containing All-Carbon Quaternary Stereogenic Centers. Methods for enantioselective conjugate addition of nucleophiles to activated olefins generating products containing all-carbon quaternary stereogenic centers are critically reviewed. Enantioselective conjugate addition has been shown to be a powerful and concise approach to construct carbon-carbon bonds to prepare compounds containing sterically hindered stereogenic centers and has seen great advances in the past several years. Owing to the difficult nature of additions to relatively unreactive conjugate acceptors, compared to additions generating tertiary stereogenic centers, and construction of a sterically-hindered bond, in many cases, new and active catalysts had to be developed. The review discusses the areas where significant advances have been made as well as current limitations and future outlook. Chapter 2 Development of New and Active Catalysts for Cu-Catalyzed Enantioselective Conjugate Addition of Alkyl- and Arylzinc Reagent. Through development of new chiral catalysts, we have found an active and enantiodiscriminating bidentate, sulfonate-containing NHC-Cu catalyst that effects enantioselective conjugate addition of alkyl- and arylzinc reagents on notoriously difficult trisubstituted cyclic enones. Products are prepared with high levels of selectivity and participate in a variety of further functionalizations. The enantioselective additions are efficient and practical, not requiring rigorously anhydrous or oxygen-free conditions. Chapter 3 Cu-Catalyzed Enantioselective Conjugate Addition of Alkyl- and Arylaluminum Reagents to Trisubstituted Enones. Outlined in this chapter is the first effective solution for Cu-catalyzed enantioselective addition of alkyl and aryl nucleophiles to trisubstituted cyclopentenones generating products bearing a β-all-carbon quaternary stereogenic center. Products are obtained in up to 97% yield and 99:1 er, only requiring 5 mol % of an in situ generated Cu-NHC catalyst. The methodology was highlighted as one of the key steps in the total synthesis of clavirolide C. Not only five-membered rings, but six- and seven-membered rings serve as proficient partners in the enantioselective process. Moreover, in cases for the enantioselective aryl addition, in situ prepared Me₂AlAr can be used without purification, filtration, or isolation, only requiring the corresponding aryl halides. The additions have also been extended to trisubstituted unsaturated lactones and chromones. Chapter 4 Cu-Catalyzed Enantioselective Conjugate Addition of Vinylaluminum Reagents to Cyclic Trisubstituted Enones. An enantioselective protocol for the formation of β,β-disubstituted cyclic ketones containing a synthetically versatile vinylsilane is disclosed. Enantioselective conjugate addition of in situ prepared silyl-substituted vinylaluminum reagents to β,β-unsaturated ketones promoted by 5 mol % of chiral Cu-NHC complexes delivers desired products with high efficiency (up to 95% yield after purification) and enantioselectivities (up to >98:<2 er). Several functionalizations utilizing the vinylsilanes, vicinal to an all-carbon quaternary stereogenic center, are shown, including an oxidative rearrangement, vinyl iodide formation and protodesilylation, accessing products not previously attainable. Furthermore, the enantioselective protocol is demonstrated as the key transformation in the total synthesis of riccardiphenol B
Thesis (PhD) — Boston College, 2011
Submitted to: Boston College. Graduate School of Arts and Sciences
Discipline: Chemistry

Amyotrophic lateral sclerosis (ALS) is a fatal disease of the nervous system. The majority of ALS cases are have no attributable genetic link, however approximately 10% are familial and 20 % of these result from mutations in the SOD1 gene. How SOD1 mutation manifests as the ALS phenotype is not clear however the enzyme does gain an aggregative property characterised by SOD1 inclusions in the brain and spinal cord. Drug treatment for sporadic and familial ALS is currently limited to palliatives and there is currently no specific treatment for SOD1 mediated ALS. In order to find molecules that may be of use in the development of SOD1 therapeutics a crystallographic screening pipeline was set up to assess binding of small molecules to both wild-type and SOD1 mutants. Using in silico studies and previous crystallographic work as a starting point, this method revealed several low molecular weight compounds (Mr 183 – 310 gMol-1) that have SOD1 binding activity. These molecules belong to three distinct classes: catecholamine, quinazoline and fluorouridine and occupy two distinct binding sites on the surface of the SOD1 β-barrel in an area known to be important in disease pathogenesis. The incorporation of copper into biological macromolecules such as SOD1 is essential for the viability of most organisms. However, copper is toxic and therefore the intracellular free copper concentration is kept to an absolute minimum. The Copper Chaperone for SOD1 (CCS) is the major pathway for SOD1 copper loading and transfer of an intrasubunit disulphide bond known to stabilise SOD1. Using small angle X-ray scattering combined with online size exclusion chromatography high quality data were acquired for both homodimeric hCCS and the functionally critical hCCS-SOD1 heterodimer. SAXS measurements were made of the hCCS complex with wild-type SOD1 and the disease relevant L38V and I113T SOD1 mutants. A rigid body modelling approach enabled exploration of the conformational dynamics of each species. Homodimeric hCCS is found to adopt positions that would facilitate initial copper acquisition and transfer from domain I to domain III. This domain III is also found in positions that would allow disulphide and copper transfer to SOD1 in the heterodimeric complex. The hCCS-I113T SOD1 complex has characteristics which are convergent with a view of ALS initiated by improperly matured SOD1.

Les dérèglements dans l'homéostasie du cuivre (Cu) ont été liés à la maladie d'Alzheimer (MA) et au cancer. Dans la MA le Cu se lie au peptide Aβ dans les plaques amyloïdes, impactant sur la production d'espèces oxygénées réactives (ROS). L'augmentation de la présence de Cu a également été impliquée dans la croissance tumorale. Ceci a conduit au développement de thérapies à base de Cu. L'utilisation de complexes de Cu pro-oxydants semble être une stratégie prometteuse pour le cancer. Dans la MA, des chélateurs qui bloquent l’activité redox du Cu sont nécessaires. Dans un environnement biologique, la stabilité d’un complex de Cu par rapport à ses concurrents physiologiques, est un aspect essentiel à considerer. Spécialement, le rôle des biomolécules liant/réductrices de Cu (telles que les métallothioneines, le glutathion et la cystéine) est très important. Cette thèse vise à étudier l’impact de ces molécules sur l’activité redox/stabilité de complexes de Cu médicinaux. Les études montrent que ces molécules sont des acteurs essentiels, car elles peuvent conduire à des réactions de dissociation, transmétallation, supprimant ainsi la production de ROS
Defects in copper (Cu) homeostasis have been linked to Alzheimer’s disease (AD) and Cancer. In AD, Cu has been found to bind to Aβ-peptides in extracellular amyloid-plaques, likely impacting the production of reactive oxygen species (ROS). Increased Cu levels have also been implicated in tumor growth. This has led to the development of Cu-based drugs. Particularly, the use of pro-oxidant Cu-complexes appears to be a promising strategy in cancer. Contrarily, in AD, redox silencing chelators are warranted. In a biological environment, the kinetic/thermodynamic stability of a Cu-complex against physiological competitors, is a key aspect to consider. In particular, the role of Cu-binding and reducing biomolecules (including metallothioneins, gluathione and cystein) is of pivotal importance. Within this context, this thesis aims to investigate the impact of these molecules on the redox-activity and stability of medicinal Cu-complexes. The studies carried out show that these molecules are key players for the fate of a Cu-complex, as they could lead to reactions of dissociation or transmetallation, abolishing the Cu-dependent ROS production

In this work, three mononuclear and five binuclear heteroleptic copper(I) complexes based on quinolin-yl-1H-1,2,3-triazole as diimine chelating ligand and DPEPhos as chelating diphosphine were successful synthesised, these compounds may be good alternative to more expensive photosensitizer based on ruthenium complexes. They show good absorption in visible region and good luminescence in solution at room temperature with long-lived excited states. The most promising complexes, which show adequate photophysical characteristics, such as high PLQY and long-lived luminescence lifetimes will be used to prove their activity in the photocatalytic reduction of CO2.

Tyrosine (4-hydroxyphenylalanine) is one of the naturally occurring 22 amino acids. The importance of tyrosine is due to the presence of its phenolic side chain. In biological systems, the tyrosyl residue in proteins is found to be sulfated, phosphorylated and nitrated. Upon oxidation with dioxygenases, Tyr residue forms dopaquinone which undergoes a series of reactions ultimately leading to the formation of melanin. Tyr is also a precursor to neurotransmitters (catechol amines namely dopamine, epinephrine and norepinephrine) and thyroid harmones T4 and T3. Tyr residue is also found to be cross linked with other amino acid residues in the active site of certain proteins. Tyr-Tyr cross link has also been associated with neurodegenerative diseases. Tyr residue in proteins has been targeted widely for site selective modifications. A series of chemical modifications like acylation, allylation, ene-type reaction, iodination with radiolabeled iodine, formation of Tyr-Tyr cross link with oxidants and aminoalkylation have been carried out on surface exposed Tyr residues in proteins. Apart from these chemical modifications of Tyr on protein surface, a couple of free Tyr-based scaffolds have also been developed for different applications. Similar to tyrosine-based scaffolds, several phenolate-based scaffolds have also been developed for various applications. Several phenolate-based binuclear metal complexes have been developed as mimics of the active site of metalloenzymes. Moreover, by varying the substituent in the phenolate scaffold, the redox properties of metal bound in these systems can be tuned. The thesis consists of five chapters. The first chapter gives general idea about tyrosine-and phenolate-based scaffolds. The first chapter also gives introduction to zinc(II)-containing enzymes metallo-β-lactamases (mβls) and phosphotriesterase (PTE) and their functional mimics. The importance of copper(II)-containing enzyme, catechol oxidase and its mimics has also been discussed. The significance and formation of o-dityrosine (Tyr-Tyr cross link) has also been briefly discussed. In chapters 2 and 3, a couple of phenolate-based ligands and their corresponding zinc(II)- and copper(II)- complexes have been synthesized and have been checked as mimics of zinc(II)-containing enzymes (mβl and PTE) and copper-containing enzyme catechol oxidase, respectively. In chapter 4, a series of tyrosine-based ligands have been designed and their in situ copper(II) complexes have been tested as mimics of catechol oxidase. In chapter 5, the effect of neighboring amino acid in the formation of Tyr-Tyr cross link has been studied. In chapter 2, a couple of zinc(II) complexes have been synthesized and studied as mimic of zinc(II)-containing enzymes mβl and PTE. Metallo-β-lactamases (mβls) are zinc(II)-containing enzymes which exist in both mono- and binuclear forms. Mβls are capable of hydrolyzing β-lactam ring in antibiotics and make them inactive (Scheme 1(A)). To date, an effective inhibitor for this enzyme is not known. Hence, in order to understand the nature of the enzyme a couple of synthetic mimics are known. However, in most of the synthetic mimics both the metal ions are in symmetrical environment. Therefore, we have attempted to design a few unsymmetrical phenolate- based ligands and their zinc(II) complexes. The unsymmetrical phenolate-based ligands HL1 and HL2 have been synthesized by sequential mannich reaction with formaldehyde and two different amines. Complexes 1 and 2 are obtained from ligands HL1 and HL2, respectively (Figure 1). For comparative purpose, the symmetrical ligands HL3 and HL4, and their zinc(II)-complexes 3 and 4 have been synthesized by reported procedures (Figure 1). The efficiency of the complexes 1-4 towards the hydrolysis of oxacillin has been studied. It has been observed that the binuclear zinc(II) complexes with metal-bound water molecule 1 and 4 are able to hydrolyze oxacillin at much faster rates compared to that of mononuclear complexes 2 and 3. However, between 1 and 4, there is no appreciable change in activity, indicating that the slight change in ligand environment has no significant role. PTE is a binuclear zinc(II)-containing enzyme, capable of hydrolyzing toxic organphosphotriesters to less toxic diesters (Scheme 1(B)). As the binuclear active site of mβl is comparable with that of phosphotriesterase (PTE), PTE activity of complexes 1-4 has been studied. Although the binuclear zinc(II)-complexes 1 and 4 are able to hydrolyze PNPDPP (p-nitrophenyl diphenyl phosphate) initially, these complexes are not able to effect complete hydrolysis. This is due to the inhibition of complexes 1 and 4 by hydrolyzed product, diester. However with mononuclear complexes 2 and 3 no such inhibitions is possible, and are capable of hydrolyzing PNPDPP at comparatively faster rates than 1 and 4. Scheme 1. Function of metallo-β-lactamase and phosphotriesterase. (A) Hydrolysis of β-lactam ring in antibiotics by metallo-β-lactamase. (B) Hydrolysis of organophosphotriesters to diesters by phosphotriesterase. Figure 1. Chemical structures of ligands HL1-HL4 and their corresponding zinc(II)complexes 1-4. In chapter 3, a couple of copper(II) complexes have been synthesized and their catechol oxidase activity has been studied. Catechol oxidase belongs to the class of oxidoreductase and it catalyzes the oxidation of a wide range of o-diphenols to o-quinones through the reduction of molecular oxygen to water (Scheme 2). A four new µ4-oxo-bridged tetranuclear copper(II) complexes (5-8) have been synthesized (Figure 2). The ability of these complexes to catalyze the oxidation of 3,5-DTBC (3,5-Di-tert-butylcatechol) to 3,5-DTBQ (3,5-Di-tert-butylquinone) has been studied. A detailed kinetic study has been carried out which reveals that the complexes with exogenous acetate ligands (5 and 6) are better catechol oxidase mimics compared to complexes with exogenous chloride ligands (7 and 8). This observation is due to the labile nature of acetate compared to chloride, as the displacement of exogenous ligand is essential for the binding of substrate to the catalyst. Based on mass spectral analysis a plausible mechanism has been proposed for the oxidation of 3,5-DTBC by these complexes. Scheme 2. Oxidation of catechol by catechol oxidase. Figure 2. Chemical structures of copper(II) complexes 5-8. In chapter 4, by following the analogy between phenol and tyrosine, a series of binucleating ligands of tyrosine or tyrosyl dipeptides (Figures 3 and 4) have been synthesized by Mannich reaction under mild conditions. The in situ complexation of these fifteen new binucleating ligands (HL5-HL19) with copper(II) chloride has been observed. In situ complexation was followed by UV-visible and mass spectral analysis. These in situ complexes were able to oxidize 3,5-DTBC at slower rate compared to that of the tetranuclear complexes reported in chapter 3. The catecholase activity has also been tested with the addition of base. A slight enhancement in activity of in situ complexes has been observed in the presence of base. Based on mass spectral evidences, a plausible mechanism for the oxidation of catechol by these in situ complexes has been proposed. Figure 3. Binucleating ligands (Mannich bases) of boc-protected tyrosine and tyrosyl dipeptides. Figure 4. Binucleating ligands (Mannich bases) of boc-deprotected tyrosyl dipeptides. In chapter 5 of the thesis, the effect of neighboring amino acid residue in the formation of o,o-dityrosine (Tyr-Tyr cross link) has been studied. o,o’-Dityrosine is a specific marker for oxidative/nitrosative stress. The increase in concentration of dityrosine is associated with several disease states. A detailed study has been carried out in order to find out the effect of neighboring amino acid residues in the rate of formation of dityrosine of several tyrosyl dipeptides. The formation of dityrosine has been carried out with horseradish peroxidase(HRP) and H2O2 (Scheme 3). Except Cys-Tyr, all other tyrosyl dipeptides, form corresponding dityrosine with HRP/ H2O2. With Cys-Tyr, the formation of corresponding disulfide is observed. The appreciably higher rate of dityrosine formation of Phe-Tyr is attributed to the presence of strong hydrophobic environment around the active site of HRP. Among the polar tyrosyl peptides, the positively charged peptides (Arg-Tyr, Lys-Tyr) undergo dityrosine formation at much faster rate compared to that of negatively charged dipepptides (Asp-Tyr, Glu-Tyr). This trend is in accordance with the pKa of neighboring amino acid residues. The positively charged neighboring residues with higher pKa stabilizes ionized tyrosine, hence the rate of dityrosine formation is higher for them. As positively charged neighboring residue enhances the rate of dityrosine formation, the effect of externally added L-Arg has been studied. A coupling of a few biologically relevant tyrosine derivatives has been studied. The derivatives in which one of the ortho-positions of tyrosine is blocked, does not undergo coupling under the experimental conditions employed. Scheme 3. Formation of dityrosine of Ile-Tyr from Ile-Tyr in the presence of H2O2 catalyzed by HRP. (For structural formula and figures pl refer the abstract pdf file)

碩士
淡江大學
化學學系碩士班
97
A series of pyridazine ligands C2-Me-(Clpdz)2 (L1) 、 C2-Me-(Ipdz)2 (L2) 、 C2-Me-(pdz-dmepzo)2 (L3) and their copper ( I ) and nickel ( II ) complexes of the types (Ni2L12) (ClO4)4 , 1 ； (Cu5L33) (ClO4)5 , 2 ； (Cu3L24) (ClO4)3 , 3 ； (NiL1)(ClO4)2 , 4 have been prepared. The complexes were produced by the reactions between ligands and Cu(CH3CN)4 ClO4 or Ni(ClO4)2 • 6H2O . All the complexes have been structurally characterized by X-ray crystallography. Complex 1 exhibits a hair-pin structure. Complexes 2 and 3 exhibits the helical structures . Complex 4 is a salt unit mononuclear Ni cation. The solution states of complexes and their self-assembling processes were examined by Uv-vis titration experiments to elucidate the reaction mechanism.

碩士
中原大學
化學研究所
106
This thesis discuss the structures and properties of Cu(I) polynuclear complexes and coordination polymers supported by the formamidinate ligands, which is divided into two parts. Part 1: Reactions of N,N’-bis(pyrimidyl-2-yl)formamidine (Hpmf), N,N''-bis(4,6-dimethylpyrimidin-2-yl)formimidamide (Hdmpmf) and N,N''-bis(4-methoxy-6-methylpyrimidin-2-yl)formimidamide (Hmmpmf) with CuX (X = Cl, Br, and I) afforded cyclic complex [Cu4(pmf)4], 1, linear copper chain {[Cu3(dmpmf)3]·CH2Cl2}, 2, cyclic complex [Cu4(mmpmf)4], 3, and compound 4 in which the structure was estimated by luminescence; complexes 1 - 3 were structurally identified by X-ray crystallography. All of the compounds follow the principle of cuprophilicity, where the distance of copper ions effect the luminescence properties. Therefore, one assumption has been proposed to estimate the structure of Cu(I) complexes that contain formamidinate ligands. The emission spectra of 1, 3, and 4 exhibit broad bands in 533 - 545 nm upon the excitation at 370 nm while the linear metal chain 2 exhibits emission at 590 upon the same excitation wavelength. Time-dependent Density function theory (TD-DFT) calculation suggests that the emissions of 1 - 4 are mainly due to metal to ligand 3dσ*/δ*→pπ*charge transfer. Part 2: One-pot hydrothermal reactions of 2-aminopyridine and triethylorthoformate and sodium hydroxide with CuX (X = Br, and I) in dimethylformamide (DMF), tetrahydrofuran (THF), and methanol (MeOH) afforded 1D extended metal atoms chain, {[Cu4(Dpyf)2Br2]･DMF}n, 5, {[Cu4(Dpyf)2Br2]･THF}n, 6, and {[Cu4(Dpyf)2I2]}n, 7, respectively, which were structurally identified by X-ray crystallography. Complexes 5 - 7 present closed-shell Cu(I)---Cu(I) interactions that are supported by formamidinate ligands. Furthermore, reversible crystal-to-crystal transformation were found in complex 5 upon the solvent exchange. The effect of cuprophilicity strongly influence the emission of compounds 5 and 7 where a board emission at 570 nm upon the excitation at 370 nm was observed for 5, while a broad emission at 549 by the excitation wavelength at 370 nm was observed for 7. Density function theory (DFT) implies that the emissions of 5 and 7 are due to metal to ligand 3dσ*/δ*→pπ*charge transfer.

碩士
國立中興大學
化學系所
105
In the research, two kinds of non-schiff-base ligands have been synthesis, N,N''-dimethyl-N,N''-bis(propanone-oxime)-ethylenediamine (ON4O) and 3,3''-(piperazine-1,4,diyl)bis(1-chloropropan-2-ol) (6-Cl), they react with dysprosium metal salts but don’t get any crystal. It inspire to remove wather from surrounding by [Dy2(μ-OH)(bsc)(NO3)2(DMF)3(H2O)] (A), then get complex 1. The unit cell of 1 comprises two similar molecules {[Dy4(bsc)4(DMF)4]、[Dy4(bsc)4(DMF)6]} (1a、1b),and magnetic susceptibility measurements of 1 has higher energy barrier Ueff = 85K than A (78K). The schiff-base ligands react with dysprosium and copper matel salts are generate dinuclear, tetranuclear and octanuclear copper complex[Cu8(hmc)4(DMF)4(NO3)2]･(NO3)2 (2･(NO3)2), [Cu4(hmb)4]･(EtOH)2 (3･(EtOH)2) and [Cu2(hmc)(DMF)2(H2O)]･(NO3) (4･(NO3)), complex 2 has a specific structure which has never been published, complex 3 has a good ctatlytic properties, complex 4 can observed a signal of S = 1 transition by electron paramagnetic resonance spectra (EPR), and complex 2 can also be observed.

碩士
國立中央大學
化學研究所
93
The design and synthesis of liquid crystals (LCs) containing heterocyclic units have been the subject of much research in recent years. Series Ⅰ: design and synthesis of Copper(Ⅱ) complexes derived from 1,3,4- thiadiazole-based containing asymmetric cores. Series Ⅱ: a novel system of symmetric dimmer liquid crystals containing benzoxazole units. All compounds were all characterized by 1H and 13C-NMR spectroscopy , their mesomorphic properties were studied by differential scanning calorimeter (DSC) ,polarized optical microscopy (POM) and temperature dependent powder X-ray diffraction. Experimental data indicated that series Ⅰ, all compounds exhibited, nematic(N), smectic A (SmA) and/or smectic C (SmC) phases, as expected by rod-like molecules. In addition, the mesomorphic properties observed by these compounds were found to be strongly dependent on the carbon chain length of terminal side chains. Both the melting and clearing points were increased with decreasing the carbon chain length. The transition temperatures of these rod-like metallo- mesogens are higher than those of the corresponding metal-free ligands. In the series Ⅱ, all compounds exhibited smectic C (SmC) phase, and when we fix the carbon number of the spacer, clearing points increased with increasing the carbon number of side chain. Odd-even effect could also be observed obviously in series Ⅱ.

Use of metal based anticancer medication began with the clinical approval of cisplatin in 1978. Research led to the development of six platinum based drug candidates which are in use around the world. However there is a great need to develop better treatment strategies. The present work entitled “Cytotoxicity of Metal Based Anticancer Active Complexes and Their Targeted Delivery Using Nanoparticles” is an effort to prepare cytotoxic metal complexes based on platinum(IV) and copper(II) and deliver them selectively to cancer cells using a targeting ligand, biotin, with two different delivery vehicles, viz. PEGylated polyamidoamine dendrimer (PAMAM) and gold nanoparticles (AuNPs). Chapter 1 provides a brief introduction to cancer and its characteristic features, followed by a short description about different treatment modalities in clinical practice. An account of the development of anticancer drugs starting from purely organic drugs to the field of metal based anticancer drugs is discussed. An overview of the available targeting strategies are discussed with specific examples. The section ends with the scope of the present work. Platinum based anticancer drugs currently in use contain platinum in the +2 oxidation state. These drugs showed side effects and are often ineffective against resistant cells, especially in the latter stages of treatment. A recent focus of metal based anticancer drug research is the development of platinum(IV) systems which shows promise to have greater activity in cancer cells in a reducing environment. Reported platinum(IV) dual drugs contain the components of “cisplatin” or an analogue along with an active organic drug. But there are no known dual drugs based on platinum(IV) that would generate a cytotoxic metal complex along with cisplatin. In Chapter 2, a bimetallic dual drug (M4) (Figure 1), the first of its kind, with components of cisplatin and copper bis(thiosemicarbazone) has been prepared (Figure 1). The components and the bimetallic complex were characterized using several spectroscopic techniques. The dual drug M4 was found to be highly cytotoxic (IC50 1.3 M) against HeLa cells and was better than cisplatin (IC50 6.8 M). The bimetallic complex turned out to be better than the mixture (IC50 7.2 M) of individual drugs which indicated possible synergism of the released cisplatin and the copper bis(thiosemicarbazone) from the dual drug. Figure 1: Structure of the platinum(IV) and copper bis(thiosemicarbazone) complexes. A novel approach towards conjugation of platinum(IV) drugs to a carrier has been developed using a malonate moiety (Figure 2). The bis(butyric acid) complex, Pt(NH3)2(OCOC3H7)2Cl2 (M1), was taken as model complex to demonstrate the conjugation strategy. The complex M4 was also conjugated to the partially PEGylated 5th generation PAMAM dendrimers. Figure 2: Schematic representation of the platinum(IV) drug conjugated PAMAM dendrimer. The cytotoxicity of M4 was reduced to a small extent on conjugation to the dendrimer. In the presence of 5 mM sodium ascorbate as a reducing agent, sustained release (40 %) of the drug was shown to occur over a period of 48 h by the drug release study. The reduction in cytotoxicity of the dendrimer conjugates could be due to incomplete release of the active drug. Unfortunately, no enhanced activity was observed with the additional targeting ligand, biotin. The drug uptake study revealed that the dendrimer conjugates were successful in entering cancer cells. There was no preferential uptake with biotin conjugated dendrimers which explained the similar cytotoxicity of dendrimer conjugates with and without biotin. Different delivery vehicles showed varied efficiency in delivering the pay load (drugs) to the cancer site. In this connection, PEGylated gold nanoparticles have shown good promise as a drug delivery vehicle. In Chapter 3, M1 and M4 are both conjugated to malonate functionalized PEGylated gold nanoparticles (30 nm). Biotin was also attached to the AuNPs for targeting HeLa cells. Figure 3: Schematic representation of the platinum(IV) drug and biotin conjugated AuNPs. The AuNPs were highly stable in water without agglomeration. There was no shift in the Surface Plasmon Resonance (SPR) band after conjugation of the drug molecules and targeting ligands. TEM images and DLS measurements showed there was no change in particle size. Drug conjugated AuNPs were also very stable in high salt concentrations as well as over a large range of pH. AuNPs with M1 were found to be less cytotoxic than the parent drug. Biotinylated AuNPs with M1 were more potent than non-biotinylated nanoparticles and increased cytotoxicity (35 %) was observed with biotin conjugation. Surprisingly, the enhanced activity of biotinylated AuNPs could not be correlated to the drug uptake study. The cytotoxicity of the bimetallic dual drug containing AuNPs were about 10-fold less and no increased activity was observed with the biotinylated conjugates. The reduced activity of AuNPs with the bimetallic drug was due to incomplete release from the AuNPs (20 % release after 48 h). But the release kinetics was very slow and sustained which might increase in vivo activity. The unexpected lower activity of biotinylated conjugates with copper bis(thiosemicarbazone) was suggestive of interference between bis(thiosemicarbazone) complex and the biotin receptor resulting in reduced drug uptake. Copper bis(thiosemicarbazone) complexes hold very good promise as a class of non-platinum anticancer drug candidates. However, they lack selectivity towards malignant cells. Recently, CuATSM has shown hypoxia selectivity and very good cytotoxicity resulting in 64CuATSM being used in advanced stages of clinical trials for imaging hypoxic cells. In Chapter 4, a copper bis(thiosemicarbazone) complex analogous to Cu(ATSM) with a redox active cleavable disulfide linker and a terminal carboxylic acid group (CuATSM-SS-COOH) was synthesised and characterised spectroscopically. The complex was highly cytotoxic and has an IC50 value (6.9 M) similar to that of cisplatin against HeLa cells. The complex was conjugated to PEGylated gold nanoparticles by amide coupling between the acid group from the drug molecule and the amine on the AuNPs (20 nm) for smart drug delivery. The gold nanoparticles were decorated with biotin for targeted delivery to the HeLa cells. Figure 4: Schematic representation of the CuATSM-SS-COOH and biotin decorated AuNPs. The CuATSM-SS-COOH was insoluble in water but conjugation to PEGylated gold nanoparticles made it water soluble. The drug molecules and biotin conjugated AuNPs were highly stable which was confirmed by TEM and DLS measurements. Similar to the study described in the previous chapter, these AuNPs were also stable in a wide range of pH and salt concentrations. In vitro glutathione (GSH) triggered release study demonstrated substantial release of the cytotoxic agent from the AuNPs (60 %) over a period of 48 h. In vitro cell viability study with HeLa cells showed reduced cytotoxicity (IC50 15 M) of AuNPs with and without biotin containing drug conjugates relative to the parent copper complex (IC50 6.9 M). The reduction of the cytotoxicity correlated well with the released amount of the active drug from the nanoconjugates over the same time period. In vivo studies demonstrated the effectiveness of these nanoparticle carriers as suitable vehicles as they exhibited nearly four-fold reduction of tumor volume without significant loss in body weight. Moreover, the biotin targeted nanoparticle showed significant (p < 0.5) reduction in tumor volume compared to the non-targeted gold nanoparticles. Thus, this smart linking strategy Can be extended to other cytotoxic complexes that suffer from non-specificity, low aqueous solubility and toxicity. Multinuclear anticancer active complexes do not act in the same way as that of their corresponding mononuclear analogues. In the case of multinuclear platinum complexes, the activity not only depends on the active moiety but also on the spacer length between the moieties. In Chapter 5, a series of multinuclear copper bis(thiosemicarbazone) complexes were prepared and characterised using different techniques. Figure 5: General structures of binuclear copper bis(thiosemicarbazone) complexes. All the complexes showed redox activity and have a very high negative reduction potential, i.e. these compounds would not be easily reduced in the biological medium and would remain as copper(II) species. As the concentration of the reducing agents are more within cancer cells, once these complexes are inside cells they would be reduced to Cu(I). These compounds were shown to be highly lipophilic from the large log P values. Unfortunately, these binuclear complexes were less active than similar mononuclear complexes. One possible reason for the reduced cytotoxicity of these complexes could be adherence of the complexes to the cell membrane due to the high lipophilicity of these complexes. Out of five different methylene spacers between two bis(thiosemicrarbazone) moieties, the complex with a three carbon spacer was shown to be the most active against HeLa cells. The complexes with five and six methylene spacers turn out to be noncytotoxic. Further experiments are necessary to reveal the mechanism of action in these complexes. In summary, bimetallic complexes can be very active and may be a way of overcoming drug resistance in platinum based therapy. A dual drug can be delivered using a malonate moiety and a disulfide linker. Gold nanoparticles are good delivery vehicles for these dual drugs and show great potential for improvement and translation to the next stage. (For figures pl refer the abstract pdf file)

The major directions of this dissertation involve (1) the syntheses and characterization of molecular polygons incorporating sp1hybridized carbon linkers and L2Pt corners (L2 = cis-1,3-diphosphine), (2) the development of protected carbon chain complexes featuring fluorous phosphine ligands and (3) click reactions of metal terminal polyynyl complexes and further metallations of the resulting triazole rings. A brief overview is provided in Chapter I. Chapter II details the syntheses of molecular squares containing bidendate diphosphine ligands of the formula R2C(CH2PPh2)2 where R = Me, Et, n-Bu, n-Dec, Bn, and p-tolCH2 (general designation dppp*), in which the R2 groups are intended to circumvent the solubility issues encountered by others. Their syntheses involve double substitutions of the dimesylate compounds R2C(CH2OMs)2 using KPPh2. Building blocks of the formulae (dppp*)PtCl2 and (dppp*)Pt((C≡C)2H)2 are synthesized and characterized, including one crystal structure of the latter. The target complexes are accessed by reactions of (dppp*)PtCl2 with (dppp*)Pt((C≡C)2H)2 under Sonogashira type conditions. Six new squares of the formula [(R2C(CH2PPh2)2)Pt(C≡C)2]4 are characterized including two crystal structures. Further topics include approaches to higher homologues and cyclocarbon synthesis. Chapter III focuses on carbon chain complexes bearing fluorous phosphine ligands of the formula P((CH2)mRfn)3 (Rfn = (CF2)n-1CF3; m/n = 2/8, 3/8, and 3/10). Precursors of the formula trans-(C6F5)((Rfn(CH2)m)3P)2PtCl are synthesized and characterized, including one crystal structure, which reveals phase separation of the fluorous and non-fluorous domains. Reactions with butadiyne give trans-(C6F5)((Rfn(CH2)m)3P)2Pt(C≡C)2H. Oxidative homocouplings afford the target complexes trans,trans-(C6F5)((Rfn(CH2)m)3P)2Pt(C≡C)4(C6F5)(P((CH2)mRfn)3)2Pt. Cyclic voltammetry indicates irreversible oxidations of the title compounds, in contrast to partially reversible oxidations of non-fluorous analogues. Chapter IV focuses on multimetallic complexes achieved by click reactions in metal coordination spheres. The copper catalyzed click reaction between trans-(C6F5)(p-tol3P)2Pt(C≡C)2H (1) and (η5-C5H4N3)Re(CO)3 affords the bimetallic 1,2,3-triazole trans-C6F5)(p1tol3P)2PtC≡CC=CHN((η51C5H4)Re(CO)3)N=N. Further reactions with Re(CO)5OTf and Re(CO)5Br give trimetallated adducts, which represent the first species of this type. An alternative route to a trimetallic complex involves the twofold cycloaddition of the diazide (η5-C5H4N3)2Fe and 1, giving (η5-C5H4NN=N-C(trans-(C≡C)Pt(Pp-tol3)2(C6F5)=CH)2Fe. The crystal structures of the di and trimetallic complexes are compared, but attempts to achieve a fourth metallation involving the =CH groups are unsuccessful. However, when the triazolium salt [trans-(C6F5)(p-tol3P)2PtC≡CC=CHN(CH2C6H5)N=N(Me)]+ I– is treated with Ag2O and [Rh(COD)Cl]2, a =CRh adduct is obtained. The success of =CH metallation is correlated to the 1H NMR chemical shift, indicative of an electronic effect.

The complexity and aggressiveness of cancer, as well as its increasing incidence and mortality worldwide, prompts the search for novel and alternative therapeutic strategies with improved effectiveness and safety. In this sense, the identification of therapeutic targets, the discovery of new molecules with antitumor potential, and the design of drug delivery systems create opportunities for a successful cancer management. Among compounds with promising anticancer activity are metal-based complexes and hybrid molecules, with some already approved for clinical use and others undergoing clinical trials or in preclinical research. In the present work, two compounds with promising anticancer potential were studied, the Cu2+ complex Cuphen [Cu(phen)Cl2] and a dual acting hybrid molecule, HM, containing two moieties – a DNA alkylating triazene and a ʟ-tyrosine analogue, 4-S-CAP, with high specificity for tyrosinase. Cuphen may act through the modulation of aquaporins (AQPs), inhibiting AQP3-mediated glycerol transport and affecting cell migration. In turn, the dual acting HM demonstrated a superior antiproliferative activity compared to the clinically approved temozolomide. Also, HM significantly inhibited tyrosinase activity and arrested cell cycle in G0/G1 phase. Following these promising in vitro results, the next goal was to maximize the in vivo therapeutic efficacy of these compounds by exploring the versatility of the most successful lipid-based nanosystem, liposomes. Long circulating liposomal formulations, with suitable physicochemical properties for each molecule, were designed and evaluated in preclinical studies. In the case of Cuphen, liposomes with pH-sensitive properties were designed to promote a locally-triggered release at the slightly acidic tumor microenvironment. In vivo, liposomal Cuphen significantly reduced melanoma and colon cancer progression, compared to free form. Furthermore, Cuphen liposomes displaying magnetic properties were successfully developed for further increase their accumulation at tumor sites upon application of an external magnetic field. For HM, an efficient incorporation in long circulating liposomes was obtained. In a subcutaneous murine melanoma model, liposomal HM remarkably reduced tumor progression, compared to free HM. Moreover, in a syngeneic metastatic melanoma model, a reduction on the number of lung metastases was observed for liposomal HM compared to all groups, including the positive control temozolomide. Remarkably, in the subcutaneous melanoma model, biodistribution studies of LIP HM showed that, 48 h post-administration, 4% of the injected dose per gram of tumor was attained, correlating with the obtained therapeutic activity. Importantly, all developed nanoformulations, for both anticancer compounds, demonstrated to be safe for parenteral administration, in healthy animals, not eliciting hepatic toxic side effects neither hemolytic activity. Furthermore, the long-term stability of liposomes in lyophilized form was achieved using an appropriate cryoprotectant. In conclusion, these encouraging results demonstrate the advantages of exploring novel therapeutic targets and compounds, particularly when associated to liposomes as a delivery system, to potentiate their safety and therapeutic effectiveness for cancer management.