Les dendrimères, font partie d'une famille particulière de polymères synthétiques, pouvant être utilisés comme nanovecteurs pour l'administration de médicaments grâce à leur structure polyvalente et leur action coopérative, ces fonctions étant confinées dans un volume de taille nanométrique. Notre groupe a récemment démontré que de petites unités dendritiques amphiphiles pouvaient s'auto-assembler en dendrimères supramoléculaires pouvant délivrer du siARN, avec une efficacité similaire à celle des dendrimères de grande génération construits de manière covalente. Dans cette thèse, ans le but de explorer des nouveaux dendrimères amphiphiles possédant des propriétés particulières d'auto-assemblage pour la délivrance de médicaments, j'ai synthétisé et caractérisé deux familles de dendrimères amphiphiles, à savoir des dendrimères bola-amphiphiliques de type PAMAM ainsi que des dendrimères amphiphiles biodégradables de type poly(aminoester). Leurs propriétés physico-chimiques et l'activité biologique pour la délivrance de siARN ont été étudiées. Nos résultats soulignent qu'elles constituent de nouveaux nanotransporteurs prometteurs pour la délivrance d'acide nucléique, voie dans laquelle nous poursuivons activement nos efforts. / Dendrimers, a special family of synthetic polymers, emerge as appealing nanovectors for drug delivery thanks to their unique precisely-controlled achitecture along with multivalency and cooperativity confined within a nanosized volume. Our group has recently demonstrated that small amphiphilic dendrons could self-assemble into supramolecular dendrimers, which mimick the covalently constructed high generation dendrimers and effectively deliver siRNA therapeutics in vitro and in vivo. In order to further explore novel amphiphilic dendrimers with special self-assembly properties for nucleic acid delivery, in this Ph.D thesis, I have synthesized and characterized two families of amphiphilic dendrimers, namely bola-amphiphilic PAMAM dendrimer and biodegradable amphiphilic poly(aminoester) dendrimer. Their physico-chemical properties and biological activity for siRNA delivery have been investigated. Our results demonstrate that they may constitute, via supramolecular self-assembling, effective and promising nanocarriers for nuclide acid delivery, in which we are actively pursuing our effort.

Cancer is lacking early detection methods and treatment specificity. In order to increase the sensitivity and specificity towards cancer cells, we propose the use of multivalent interactions targeting specific receptor combinations at the cancer cell surface. In this thesis, we explored the design of multimers, which could provide such interactions. The design was investigated and revisited based on specific parameters, essential for the creation of multivalent interactions such as thermodynamics. The synthesis was designed so that libraries of homo- and hetero-multimers of different valencies can be obtained efficiently with good yields. The established synthetic scheme is empowered by its modularity, necessary to investigate different essential factors. Trimers composed of micromolar affinity MSH(4) targeting the MC1-R, overexpressed in melanoma, were investigated on a model cell line and resulted in the creation of nanomolar affinity constructs with up to 350 fold increase in affinity. Different multimers such as hexavalent and nonavalent dendrimers were synthesized and studied for their properties. All constructs had nanomolar affinity and showed to be non-toxic up to micromolar concentrations and imaging studies also confirmed their internalization, which overall demonstrate the potential for these compounds to be used as markers for cancer cells and as delivery agents. Trimers targeting the CCK2-R were similarly investigated for their potential as pancreatic cancer markers. However, those constructs did not seem to result in the expected enhancements in affinity, but the affinity of the initial monovalent agonist was in the 10-50 nanomolar range. As we were unable to design micromolar affinity agonist we investigated the use of antagonists. This study, revealed the importance of thermodynamics in the creation of multivalent interaction. Heterotrivalent ligands (CCK and MSH) were investigated for their potential in cross-linking different receptors and the study demonstrated the subtility to detect cross-linking. Finally, the different attempts toward the efficient synthesis of a tetra-orthogonal scaffold, a key feature needed to generate multimers that could target up to 3 different receptors was investigated and showed promising results. It is our hypothesis that such an approach will ultimately lead to specific markers of tumor cells, which could be used as diagnosis agents when modified with an imaging moiety and as a therapeutic agent when modified with a drug.

M.Tech. (Chemistry) / Please read abstract in the full-text document

A Cubebina (CB) é uma lignana da classe das dibenzilbutirolactonas presente em uma ampla variedade de espécies vegetais espalhadas pelo mundo. Nos últimos anos, vários estudos têm demonstrado seu potencial para o tratamento de doenças como Leishmaniose e Doença de Chagas, além de possuir ação antiinflamatória e analgésica. Entretanto, apesar da CB apresentar diversas potencialidades terapêuticas, sua utilização ainda é limitada devido à sua baixa solubilidade em água, que compromete sua biodisponibilidade. Os dendrímeros são estruturas quase esféricas, de dimensão nanométrica, com grande número de subgrupos funcionais reativos e espaços interiores protegidos. São capazes de complexar com moléculas e, dessa forma, aumentar a solubilidade do fármaco. De forma semelhante, as ciclodextrinas (CDs) são oligossacarídeos cíclicos que possuem a capacidade de interagir com moléculas hidrofóbicas através de sua cavidade que também é hidrofóbica. Isso as torna capazes de aumentar a solubilidade de fármacos pouco solúveis aumentando sua biodisponibilidade. Nesse trabalho foram obtidos complexos dessas macromoléculas com a CB por diferentes métodos. Metodologias de quantificação da CB, nas formas livre e complexada, foram desenvolvidas utilizando técnicas de espectrofotometria e de cromatografia líquida de alta eficiência. Esses sistemas foram caracterizados utilizando técnicas apropriadas como estudos de solubilidade de fase, espectroscopia no IV, difração de raios X, RMN H1 e simulações de modelagem e dinâmica molecular. Os resultados demonstraram que tanto os dendrímeros quanto as ciclodextrinas são capazes de gerar complexos solúveis com a CB sendo os melhores resultados obtidos com a HP--CD. Os resultados desse trabalho permitiram concluir que tanto dendrímeros quanto CDs são estruturas adequadas e promissoras para a veiculação da CB, aumentando assim o seu potencial para aplicações biológicas, visando o tratamento de diversas patologias. / Cubebin (CB) is a lignan from the class of dibenzylbutyrolactones present in a wide variety of plant species around the world. Its known for its anti-inflammatory and analgesic effects. In recent years, several studies have demonstrated its potential to treat diseases such as leishmaniasis and Chagas. Although the CB shows several potential therapeutics, its use is still limited due to its low water solubility which compromises its bioavailability. The dendrimers are nearly spherical structures, nanometer-sized, with large number of reactive functional groups and protected inner. They are capable of complexing with molecules and thereby increase the solubility of the drug. Similarly, cyclodextrins (CDs) are cyclic oligosaccharides that have the ability to interact with hydrophobic molecules through the cavity which is also hydrophobic. This makes them capable of increasing the solubility of poorly soluble drugs by increasing their bioavailability. In this work, complexes of macromolecules with CB were obtained by different processes. Methodologies for quantification of free and complexed CB were developed by spectrophotometry and high performance liquid chromatography. Moreover, these systems were characterized by techniques such Phase Solubility Studies, IR spectroscopy, X-ray diffraction, NMRH1, modeling and molecular dynamics simulation. The results showed that both dendrimers and cyclodextrins are capable to form soluble complexes with CB. Best results were obtained with HP--CD. The findings of this study indicate that both dendrimers and CDs are appropriated structures to release the CB and also increase its potential for biological applications, focusing on the treatment of various diseases.

Philosophiae Doctor - PhD / The continuous increase in energy consumption and decrease in fossil fuels reserves are a primary concern worldwide; especially for South Africa. Therefore, there is an urgent need for alternative energy resources that will be sustainable, and environmentally friendly in order to tackle the ecological degradation generated by the use of fossil fuels. Among many energy ‘niches’, solar energy appears to be one of the most promising and reliable for the African continent because of the constant availability of sun light. Organic conjugated polymers have been identified as suitable materials to ensure proper design and fabrication of flexible, easy to process and cost-effective solar cells. Their tendency to exhibit good semiconducting properties and their capability to absorb photons from the sunlight and convert it into electrical energy are important features that justify their use in organic photovoltaic cells. Many different polymers have been investigated as either electron donating or electron accepting materials. Among them, poly(3-hexylthiophene) is one of the best electron donor materials that have been used in organic photovoltaic cells. It is a good light absorber and its Highest Occupied Molecular Orbital (HOMO) energy level is suitable to allow electron transfer into an appropriate electron acceptor. On the other hand, the molecular ordering found in dendrimers attracted some interest in the field of photovoltaics as this feature can ensure a constant flow of charges. In this work, I hereby report for the first time, the chemical synthesis of a highly crystalline dendritic star copolymer generation 1 poly(propylene thiophenoimine)-co-poly(3-hexylthiophene) (G1PPT-co-P3HT) with high molecular weight and investigate its application as donating material in bulk heterojunction organic photovoltaics.

WHO has reported that antibiotic resistance is the third major cause of human death all over the globe. Recent study, has focused on the development of new antibacterial resistance drugs. Herein, we tried to synthesis a series of polymers that can mimic the HDPs. HDPs can target the bacterial cell membrane and they have less chances to develop bacterial resistance. We synthesized the amphiphilic polycarbonates that are highly selective to Gram-positive bacteria, including multidrug resistant pathogens. The membrane disruption activity of these polymers was proved by fluorescence and TEM studies and the drug resistance study showed that the polymers don’t develop bacterial resistance. In order to further design the molecules that can target a broad spectrum of bacteria, we have designed a series of lipidated dendrimers that can target the Gram-positive and Gram-negative bacteria. These dendrimers mimic the HDPs and target the bacterial cell membrane. Dendrimers are reported to inhibit the formation of bacterial biofilm which makes them promising for their future development of antibiotic agents. Apart from the synthesis of polymers and dendrimers as antibacterial agents, we have designed a series of small molecular antibacterial agents that are based on the acylated reduced amide scaffold and small dimeric cyclic guanidine derivatives. These molecules display good potency against a panel of multidrug-resistant Gram-positive and Gram-negative bacterial strains. Meanwhile, they also effectively inhibit the biofilm formation. Mechanistic studies suggest that these compounds kill bacteria by compromising bacterial membranes, a mechanism analogous to that of host-defense peptides (HDPs). Lastly, we also demonstrate that these molecules have excellent in vivo activity against MRSA in a rat model. This class of compounds could lead to an appealing class of antibiotic agents combating drug-resistant bacterial strains.

In this work flow properties of dendrimers are studied with the aid of molecular simulations. For the first time the results of the nonequilibrium molecular dynamics simulations of the dendrimers in the melt are reported. Molecules are modelled at the coarse-grained level using the bead-spring model. The objective of this research is to analyse the influence of the molecular topology in the macroscopic flow behaviour of the melts. Systems of dendrimers of generations 1 to 4 undergoing planar shear are compared to the melts composed of linear chain polymers. The internal structure and shape of dendrimers is extensively analysed. The response of the molecules to the shearing in the form of stretching and alignment is studied. The correlation between the onset of shear thinning and the onset of deformation of molecules is observed. The changes in the fractal dimensionality of dendrimers due to shearing are also analysed. Dendrimers, due to their highly branched structure and compact globular conformations in the melt, are found to behave differently when sheared, compared to traditional linear polymers. Unlike linear polymers, they do not undergo transition form the Rouse to the reptation regimes. This effect is explained in terms of the suppressed entanglement between molecules. Moreover, dendrimers when compared to linear chain systems exhibit lower Newtonian viscosity, onset of the shear thinning at higher strain rates, and less pronounced shear thinning in the non-Newtonian regime. They can be used as rheology modifiers, as it is shown in the preliminary results obtained from the simulations of the dendrimers-linear polymer blends. In agreement with other theoretical and experimental studies, dendrimers in the melt are found to have compact space-filling structure with terminal groups distributed throughout the interior of the molecule. Suggestions for the further study of dendrimers via molecular simulations are made.

For more than 150 years, since the synthesis of urea by Friedrich Wöhler in 1828, molecular chemistry has developed a vast array of highly sophisticated and powerful methods for the construction of more complex molecular structures. Beyond the molecular chemistry based on the covalent bond, there lies the field of supramolecular chemistry, aims to gain control over the intermolecular bond. Supramolecular species are characterized both by the spatial arrangement of their components and by the nature of the intermolecular bonds that hold these components together. They possess well-defined structural, conformational, thermodynamic and kinetic properties. Research has been focused on utilization of such confined spaces to manipulate reaction dynamics, properties of the encapsulated guest molecules. This research presented in this thesis is a consolidated account of photophysical and photochemical reactions carried in water-soluble macrocycles, cavitands and dynamic host systems such as dendrimers and micelles. With the aid of NMR (1D and 2D) spectroscopic techniques, the host-guest complex characterization is executed.

Metal ions are important for medical, environmental and catalytic applications. They are used as precursor molecules for the manufacture of metal nanocatalysts, which are promising materials for an array of biomedical, industrial, and technological applications. Understanding the effect of the environment upon a metal ion-dendrimer system constitutes a step closer to the understanding of the liquid phase templated synthesis of metal nanoparticles. In this dissertation we have used computational techniques such as abinitio calculations and molecular dynamics (MD) simulations to investigate the complexation of Cu(II) and Pt(II) metal ions to a polyamidoamine (PAMAM) dendritic polymer from structural, thermodynamic, and kinetic viewpoints. First, we analyze the local configuration of a low generation polyamidoamine dendrimer to understand the role of intramolecular interactions. Then, we examine the local configuration of dendrimer outer pockets in order to determine their capacity to encapsulate water within. Next, the complexation of Cu(II) with a small –OH terminated dendrimer in presence of solvent and counterions is investigated. This relatively simple system gives insight on how cationic species bind within a dendrimer. The complexation of potassium tetrachloroplatinate, commonly used precursor salt in dendrimer templated synthesis of platinum and bimetallic platinum-containing nanoparticles, with PAMAM dendrimer has been the subject of several experimental reports. So we investigate the complexation of potassium tetrachloroplatinate within a dendrimer outer pocket in order to understand the effect of dendrimer branches, Pt(II) speciation, pH, solvent and counterions upon it. Our study shows that dendrimer branches can improve the thermodynamics but can also preclude the kinetics by raising the energy barriers. Our study provides an explanation of why, where Pt(II) and how Pt(II) binds. We believe that these molecular level details, unaccessible to experimental techniques, can be a helpful contribution toward furthering our understanding of the complexation of Pt(II) and the starting point to study the next step of dendrimer templated synthesis, the reduction of Pt(II) into platinum nanoparticles inside pockets.

Functional Dendritic Structures from Bile Acids: Supramolelcular Hosts, Light Harvesters and Drug Carriers Chapter 1. An Overview of Functional Dendrimers. Dendrimers are welldefined, hyperbranched macromolecules that are prepared by highly controlled iterative methodologies. The ability to modulate the size, molecular weight, chemical functionalities and the position and number of functional groups in dendrimers make them promising candidates for a wide variety of applications. In this chapter, three areas 1) hostguest chemistry 2) light harvesting and 3) drug delivery, where dendrimers are increasingly finding applications, are discussed with selected examples. Chapter 2. Hydroxyl Terminated Dendritic Oligomers from Bile Acids: Synthesis and Properties. Bile acids are excellent building blocks for dendritic construction because of their many interesting features. They are readily available, chiral, facial amphiphiles with complementary functionalities. Moreover, due to the large size of the bile acid units, a dendritic structure consisting of only a few such repeat units can have an extended structure with multiple functionalizable groups. (figure 1) The high reactivity of the chloroacetyl group has been exploited for the synthesis of bile acid based first and second-generation dendrons with glycolate linkers and multiple hydroxyl groups. The synthesis involves only a few steps and avoids the use of protecting groups for the terminal hydroxyl groups. The synthesis of a bile acid tetramer is shown here as an example (Figure 1). Carboxyl protected cholic acid was reacted with chloroacetylchloride to generate the trischloroacetylated derivative. This compound on reaction with excess of sodium cholate generated the tetramer with nine hydroxyl groups via displacement of the chlorides. In order to synthesize higher generation dendritic structures, perchloroacetylated firstgeneration dendrons were first synthesized. These were subsequently reacted with excess of sodium deoxcholate to generated secondgeneration dendrons with multiple hydroxyl groups (Figure 2). All the compounds were characterized by H NMR, C NMR, IR, ESIMS/MALDI-TOF, HPLC and elemental analysis(wherever possible) Figure 2. Structure of tridecamer. These dendritic structures with facially amphiphilic bile acid backbones on the periphery were able to solubilize cresol red, a hydrophilic dye, in a nonpolar solvent, thus exhibiting reverse micellar characteristics. Chapter 3. Multiple Naproxen Appended Bile Acid Dendrimers as Light Harvesters and Drug Carriers. Part I. Synthesis and Characterization. Using the same synthetic strategy as in Chapter 2, bile acid based dendritic structures appended with multiple bioactive (S)naproxens were generated as potential drug carriers. The construction of these dendrimers was accomplished using per(chloroacetylated) bile acid dendrons and conveniently displacing all the chlorides with naproxen units. Since naproxen is photoactive with a high fluorescence quantum Figure 3. Structures of secondgeneration dendrimers and a monomer with multiple naproxens. yield, the photophysical properties of these multichromophoric dendrimers could be further explored (Figure 3). By functionalizing the carboxyl group on the side chain with an anthracenyl moiety the energy transfer properties of these dendrimers could be studied. In this section the synthesis of first and secondgeneration dendritic structures with multiple naproxen units at the periphery and benzyl/anthracenyl moiety on the side chain are described (Figure 3). Model compounds using monomeric bile acid units were synthesized for comparison with the dendritic structures. All the compounds were characterized by H NMR, C NMR, IR, ESIMS/MALDITOF, HPLC and elemental analysis (wherever possible). Part II: Absorption, Fluorescence and Intramolelcular Energy Tranfer Studies. Absorption studies showed that the molar extinction coefficients increase linearly with increasing number of naproxen units and the absorption spectra of anthracenyl moiety remain unchanged in all the dendritic systems. These indicated the absence of ground state interaction between the chromophores. In the 275-290 nm absorption region, the molar extinction coefficient of naproxen is much greater than that of the 9-anthracenylmethyl chromophore. Hence excitation in this region would mainly excite the naphthalene chromophore. Upon excitation at 275 nm, there was predominant emission from the anthracenyl moiety in the dendritic structures (containing both chromophores) and the fluorescence intensity increased with increasing number of naproxens(Figure4). This indicated that the dendrimers act as efficient light harvesters with energy transfer from naproxen to anthracene (intramolecular nature of the energy transfer was confirmed through control experiments). (Figure 4: Refer PDF File) The fluorescence and energy-transfer properties were further investigated by time-resolved fluorescence spectroscopy. The presence of fast decay component(s) in the naproxen decay in dendritic structures (containing both chromophores) indicates that its fluorescence is quenched in the presence of anthracene due to energy transfer ((λex 275 nm, λem 350 nm (Figure 5). This was further confirmed by monitoring the fluorescence of the sensitized anthracenyl chromophore (λex 275 nm, λem 436 nm) which exhibited a fast rise comparable to he quenched naproxen lifetime(s). The efficiency of energy transfer was estimated by donor quenching by both steadystate and timeresolved techniques. The dendritic structures exhibited high energy transfer efficiencies (~ 70 – 90 %) with the net efficiency decreasing from the first to second-generation. Part III. In vitro Study of Hydrolysis of Naproxen Appended Bile Acid Prodrugs by Chemical and Enzymatic Methods. The naproxen appended bile acid dendrimers consist of hydrolyzable ester and glycolate linkers. Hence the chemical stability and enzymatic degradation with possible release of naproxen was studied. Two compounds, monomer appended with two naproxens and trimer with four naproxens have been used for the initial investigations (Figure 6). The compounds were found to be highly stable towards chemical hydrolysis and did not show any hydrolysis in phosphate buffer, pH = 7.4 even after 7 days. Since the compounds were not soluble in water, Arabic gum and TritonX were used for emulsification. Figure 6. Structures of monomer and trimer. (Refer PDF File) The enzymatic hydrolysis of the compounds was then studied using Candida Rugosa Lipase. In both cases, there was slow hydrolysis of the substrate and intermediates were formed (with release of free naproxen) which were detected by HPLC (reverse phase column with a UV detector). The trimer underwent much slower hydrolysis compared to the monomer. The intermediates were characterized by absorption and mass (ESIMSQTOF) spectrometry.