Theory has been used to complement experiment in the development of both drugs and delivery systems. Theoretical methods are capable of identifying the molecular basis of drug formulation inadequacies and systematic theoretical studies may suggest fruitful avenues for material modification. This thesis highlights the utility of computer-based theoretical calculations for guiding the design of drug formulations and enhancing material-drug compatibility and stability. Specifically, the present work explores the applications of semi-empirical methods and atomistic molecular dynamics (MD) simulations to enhance the performance of nano-emulsions and polymer micelle formulations for the delivery of hydrophobic drugs. This work includes three separate studies preceded by an introductory summary of available theoretical techniques. The first study evaluates the accuracy and reliability of semi-empirical methods and MD simulations as means to select suitable excipients to formulate the anti-cancer drug docetaxel in an emulsion. Here, simulations accurately predict the rank order of drug solubility in various excipients, suggesting that simulation is useful for library enrichment. In the second study, a drug conjugation approach is used to further improve the stability and solubility of docetaxel in a triglyceride-based nano-emulsion. Here, optimal conjugates are identified with computer-based theoretical calculations and conjugates with formulation-compatible moieties are synthesized. As predicted, the conjugates exhibit enhanced solubility and loading efficiency in a nano-emulsion. The goal of the third study is to rationally design a stable unimolecular star copolymer that, as a unimer, does not disassemble upon the dilution that accompanies intravenous injection. Here, MD simulation is used to systematically investigate the solution properties of differently composed star copolymers. Overall, star copolymers with a hydrophobic PCL core ≤ 2 kDa and hydrophilic PEG blocks approaching 14.6 kDa per arm are predicted to form unimolecular micelles that remain unimeric at high concentrations. The studies presented in this thesis demonstrate that theoretical approaches are useful for fast pre-screening of drug formulation materials and for the development of delivery systems and drug derivatives.

Suite au succès clinique des composés du platine (cisplatin et de ses dérivés) en tant qu’agent anticancéreux, la chimie inorganique médicinale a connu un essor considérable offrant ainsi une alternative à la conception d'agents thérapeutiques. Bien que le cisplatin et ses dérivés soient sans doute une des classes la plus réussie de médicaments anticancéreux, leur utilisation n’est pas efficace contre tous les types de cancer. De plus, ils sont à l’origine d’effets secondaires très invalidants (neurotoxicité, néphrotoxicité, perte de poids, nausées…) et sont également inactifs contre certains cancers présentant une résistance innée ou induite. Par conséquent, la recherche a développé des composés possédant des activités améliorées et des profils de toxicité plus acceptables. Ceci a ainsi stimulé l'intérêt pour les complexes contenant d'autres métaux de la mine du platine tels que le ruthénium, car ces composés présentent une plus faible toxicité que les complexes existants. Certains composés du ruthénium ont déjà montré une activité anticancéreuse prometteuse et deux complexes du RuIII le trans-[RuCl4-(DMSO)(Im)]ImH (NAMI-A) et le trans-[RuCl4(Ind)2]IndH (KP1019) sont entrés récemment en phase clinique.Dans le but d’améliorer l’activité et de réduire les effets secondaires des agents anticancéreux existants, le Laboratoire de Synthèses Métallo-Induites a développé depuis plusieurs années des complexes organométalliques du ruthénium RDC (Ruthenium Derivative Compound) dans lesquels un des ligands est fortement lié au métal par une liaison convalente σ C-Ru qui est elle-même stabilisée par une liaison intramoléculaire N-Ru. Cette thèse présente les avancées récentes du laboratoire dans ce domaine et plus particulièrement le développement d’une chimiothèque de RDC de seconde génération dans laquelle le ligand cyclométallé est stabilisé par deux liaisons N-Ru. Plusieurs complexes ont ainsi atteint des IC50 significativement inférieur à la micromole. En parallèle, le même type d’études a été réalisé sur des complexes de l’osmium aboutissant à une chimiothèque ODC (Osmium Derivative Compound) d’une quarantaine de composés. Cette étude est d’un intérêt particulier car non seulement elle complète la famille des RDC, mais elle permet également de vérifier l’impact du changement de métal. Les études biologiques ont ainsi montré que l'osmium présente un réel intérêt dans le développement de nouveaux médicaments antitumoraux particulièrement efficaces. Les mesures des propriétés physico-chimiques telles que le potentiel d’oxydo-réduction et la lipophilie (log(Po/w)) ont permis de corréler ces paramètres à leur activité in vitro, se rapprochant ainsi d’une éventuelle relation propriété-activité (P.A.R.). Le réel rôle du potentiel d’oxydo-réduction deviendra probablement plus clair au fur et à mesure de notre avancée dans la résolution du mécanisme d'action de ces espèces. / Since the clinical success of platinum drugs (cisplatin and its derivatives) as anticancer agent, medicinal inorganic chemistry has become a field of growing interest because it offers an alternative for the design of therapeutic agents that are not readily available to organic compounds. Although cisplatin is one of the most widely used drugs in chemotherapy, it is not effective for all types of cancer. Moreover, platinum drugs are the cause of disabling side effects (neurotoxicity, nephrotoxicity, weight loss, nausea…) and their applicability is limited by innate or induced resistance to platinum in a narrow range of tumours. Therefore, this clinical success has promoted the search for cytotoxic compounds with enhanced activities and more acceptable toxicity profiles. This has stimulated interest in complexes containing other heavy metals of the platinum group such as ruthenium because these compounds show lower toxicity than drugs based on platinum. Some ruthenium compounds have already shown promising anticancer activity and two RuIII complexes trans-[RuCl4-(DMSO)(Im)]ImH (NAMI-A and trans-[RuCl4(Ind)2]IndH (KP1019) recently enter in clinical phase for their respectively antimetastatic and cytotoxic properties.In the essential aim of increasing activity and reducing side effects of anticancer agents, the Laboratoire de Synthèses Métallo-Induites has developed for several years organometallic ruthenium compounds RDC (Ruthenium Derivative Compound) in which one of the ligand is strongly bound to the metal via a strong σ C-Ru bond and stabilized by an intramolecular N-Ru bond. This thesis presents the recent advances of the laboratory in this field and the development of a second generation RDC in which the cylometallating ligand is stabilized by two N-Ru bonds. Thus, several complexes pass the symbolic barrier of the nanomolar range for their IC50 indicating a critical improvement. At the same time, we decided to focus our studies on osmium heavier congener, not only to complete the RDC chemical library, but also to verify the impact of exchanging the metal. An extensive chemical library ODC (Osmium Derivative Compound) of forty cyclometalated osmium complexes was synthesized and evaluated in vitro. Biological studies on these ODCs showed that osmium is another metal that deserves attention for the development of new effective antitumour drugs. The measurements of physicochemical properties such as red-ox potential and lipophylicity (log(Po/w)) allowed us to tentatively correlate these parameters to the level of activity, thus approaching a possible Property-Activity Relationship (P.A.R.). More insight into the role of the red-ox potential will probably become clearer as we progress into the mechanism of action of these species.

Submitted by Renata Lopes (renatasil82@gmail.com) on 2017-04-18T17:37:33Z No. of bitstreams: 1 wiliamcaneschi.pdf: 24031147 bytes, checksum: 55a6b3c64e0dad5d05212886301c8aa2 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2017-04-19T11:42:35Z (GMT) No. of bitstreams: 1 wiliamcaneschi.pdf: 24031147 bytes, checksum: 55a6b3c64e0dad5d05212886301c8aa2 (MD5) / Made available in DSpace on 2017-04-19T11:42:35Z (GMT). No. of bitstreams: 1 wiliamcaneschi.pdf: 24031147 bytes, checksum: 55a6b3c64e0dad5d05212886301c8aa2 (MD5) Previous issue date: 2016-12-20 / CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Os heterociclos oxadiazólicos estão presentes em inúmeras estruturas com diversas propriedades biológicas, por esse motivo, o interesse nessa pesquisa. Desse modo, este trabalho encontra-se dividido em dois capítulos: o primeiro refere-se a síntese de oxadiazóis com intuito de verificar seu potencial biológico, enquanto o segundo, baseia-se no desenvolvimento de novas metodologias para síntese dos derivados 1,2,4 e 1,3,4oxadiazólicos. No primeiro capítulo, vinte e uma substâncias derivadas do heterociclo 1,2,4oxadiazólico foram obtidas por meio de reações de substituição nucleofilica de segunda ordem e trinta e dois novos derivados 1,3,4-oxadiazólicos foram obtidos a partir de reações do tipo Mannich. Os compostos foram testados quanto as suas propriedades citotóxicas e antibacteriana. De um modo geral, os derivados 1,2,4-oxadiazólicos não apresentaram interessantes atividades biológicas. Por outro lado, os regioisômeros 1,3,4- demonstraram um perfil de atividade interessante, sendo mais ativas que aquelas moléculas contendo o grupo piperazina alquilado com doze átomos de carbono. Para a atividade antitubercular, foi verificada uma melhor atividade para os 1,3,4-oxadiazóis alquilados com quatorze átomos de carbono. A busca cada vez maior por metodologias mais simples e eficientes na síntese de novas substâncias, propiciou, neste segundo capítulo, a síntese de uma série de derivados 1,2,4- e 1,3,4-oxadiazólicos obtidos por reações de aminocarbonilação catalisadas por paládio. Vários nucleófilos hidrazidas e amidoximas foram passíveis de reação com diferentes brometos de arila e monóxido de carbono produzido ex situ, em uma reação multicomponente, possibilitando a formação desses heterociclos em altos rendimentos. Essa metodologia se mostrou eficaz na marcação isotópica de ¹³C para diferentes compostos bem como permitiu a síntese do fármaco ataluren com rendimento global de 43%. / Oxadiazoles heterocycles are present in many structures with different biological properties, therefore, the interest in this research. So, this work is divided in two chapters: the first refers to the synthesis of these heterocycles in order to verify its biological potential, while the second is based on the development of new methodologies for synthesis of derivatives 1.2, 4 and 1,3,4-oxadiazoles. In the first chapter, twenty one 1,2,4-oxadiazoles derivatives were obtained by nucleophilic substitution reactions of second order and thirty two new 1,3,4oxadiazoles derivatives were obtained through Mannich-type reactions. The compounds were tested for their anticancer and antibacterial properties. In general, 1,2,4-oxadiazoles derivatives did not show interesting activity against the tested pathologies. On the other hand, 1,3,4-regioisomers demonstrated interesting activity profile, being most active those molecules containing the alkylated piperazine group with twelve carbons chain. For the antitubercular activity, a better activity was verified for the alkylated 1,3,4oxadiazoles with fourteen carbon chain. The search for efficient and simple methods for the synthesis of new molecules, allowed in the second chapter, the synthesis of a number of 1,2,4- and 1,3,4-oxadiazoles derivatives obtained by reactions palladium-catalyzed aminocarbonylation reactions. Various nucleophiles hydrazides and amidoximes were able of reaction with different aryl bromides and carbon monoxide produced ex situ in a multicomponent reaction, enabling the formation of such heterocycles in high yields. This methodology was effective for isotopic ¹³C labeling for different compounds as well as allowed the synthesis of the drug ataluren in an 43% overall yield.

<p>Capillary Electrophoresis (CE) was explored as a means for physicochemical and biopharmaceutical characterisation of small drug molecules. Special attention was paid to the characterisation of acid-base and lipophilic properties of drug compounds by analysing their migration behaviour in different CE systems. The thesis comprises an overview of the field together with separate studies on the different topics.</p><p>The utility of CE for the determination of pK_a of labile drug compounds was investigated. A general methodology was developed comprising key steps such as the use of a stabilising sample diluent, electromigration injection, and analyte characterisation by UV-Vis spectroscopy. The methodology was successfully applied for two sets of drug compounds, labile at low and high pH, respectively.</p><p>CE was also evaluated for experimental modelling of passive intestinal membrane permeability by studying analyte migration in liposomal, microemulsion and micellar electrolytes. Good correlation is reported between CE migration and Caco-2 cell absorption estimates and for in vitro inhibition of thrombin. Interestingly, a slightly better correlation was obtained for liposomal electrolytes.</p><p>The utility of liposomes in CE was further extended by developing a novel procedure for immobilising liposomes inside fused silica capillaries. This approach enabled direct on-line coupling of liposome CE to high sensitivity mass spectrometry. The utility of liposome-coated capillaries is demonstrated for estimating drug passive intestinal membrane permeability. Its use in biopharmaceutical drug profiling is discussed.</p><p>Utilising advanced molecular descriptors, commonly applied to in silico prediction of passive intestinal membrane permeability, migration of analytes in micellar CE systems could be well predicted. The novel approach was based on hierarchical multivariate analytics and use of molecular descriptors for both analytes and micellar media surfactants. Demonstrated results propose that the CE format could be useful to validate how representative molecular descriptors are for describing molecular behaviour in complex liquid media, e.g. physiological systems.</p>

Capillary Electrophoresis (CE) was explored as a means for physicochemical and biopharmaceutical characterisation of small drug molecules. Special attention was paid to the characterisation of acid-base and lipophilic properties of drug compounds by analysing their migration behaviour in different CE systems. The thesis comprises an overview of the field together with separate studies on the different topics. The utility of CE for the determination of pKa of labile drug compounds was investigated. A general methodology was developed comprising key steps such as the use of a stabilising sample diluent, electromigration injection, and analyte characterisation by UV-Vis spectroscopy. The methodology was successfully applied for two sets of drug compounds, labile at low and high pH, respectively. CE was also evaluated for experimental modelling of passive intestinal membrane permeability by studying analyte migration in liposomal, microemulsion and micellar electrolytes. Good correlation is reported between CE migration and Caco-2 cell absorption estimates and for in vitro inhibition of thrombin. Interestingly, a slightly better correlation was obtained for liposomal electrolytes. The utility of liposomes in CE was further extended by developing a novel procedure for immobilising liposomes inside fused silica capillaries. This approach enabled direct on-line coupling of liposome CE to high sensitivity mass spectrometry. The utility of liposome-coated capillaries is demonstrated for estimating drug passive intestinal membrane permeability. Its use in biopharmaceutical drug profiling is discussed. Utilising advanced molecular descriptors, commonly applied to in silico prediction of passive intestinal membrane permeability, migration of analytes in micellar CE systems could be well predicted. The novel approach was based on hierarchical multivariate analytics and use of molecular descriptors for both analytes and micellar media surfactants. Demonstrated results propose that the CE format could be useful to validate how representative molecular descriptors are for describing molecular behaviour in complex liquid media, e.g. physiological systems.

Submitted by Renata Lopes (renatasil82@gmail.com) on 2016-02-25T13:51:08Z No. of bitstreams: 1 celsodeoliveirarezendejunior.pdf: 4187877 bytes, checksum: e397d45f85368ea5d9904f085b86462e (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2016-03-03T13:29:51Z (GMT) No. of bitstreams: 1 celsodeoliveirarezendejunior.pdf: 4187877 bytes, checksum: e397d45f85368ea5d9904f085b86462e (MD5) / Made available in DSpace on 2016-03-03T13:29:51Z (GMT). No. of bitstreams: 1 celsodeoliveirarezendejunior.pdf: 4187877 bytes, checksum: e397d45f85368ea5d9904f085b86462e (MD5) Previous issue date: 2014-07-18 / CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Neste trabalho são descritas as sínteses e avaliações biológicas de diferentes classes de compostos orgânicos e está dividido em três capítulos. O primeiro deles descreve a síntese de derivados da genisteína com distintas propriedades físico-químicas, a fim de avaliar a influência dessas propriedades na atividade biológica contra a esclerose múltipla. Foram sintetizados compostos condensados a carboidratos derivados da D-glicose e D-galactose e derivados lipofílicos com cadeias alquila ou acila lineares de doze ou quatorze carbonos. Esses compostos foram submetidos a ensaios de citotoxicidade e anti-inflamatórios in vitro e os compostos mais ativos foram avaliados quanto a sua atividade na modulação da resposta imune in vivo no modelo de encefalomielite auto-imune experimental (EAE). Na síntese dos drivados éteres verificaram-se diferentes reatividades: os compostos com cadeias alquila lineares foram obtidos em rendimentos melhores, seguido dos derivados da D-glicose e D-galactose, respectivamente. A regiosseletividade obtida na síntese dos derivados éteres foi sugerida por nOe, enquanto que nos derivados ésteres foi sugerida por RMN de 1H. Os ensaios biológicos revelaram que todos os compostos apresentaram atividade in vitro e os derivados de carboidrato foram mais citotoxicicos que os derivados com cadeias lipofílicas lineares. Após os ensaios in vivo, o composto 13 foi considerado um protótipo para o tratamento da esclerose múltipla. O segundo capítulo descreve a síntese e avaliação das propriedades antimicrobianas de surfactantes derivados do ácido quínico condensados a diaminas N-alquiladas, variando-se o tamanho da cadeia alquila (parte apolar) e a estrutura do ácido quínico (parte polar), estabelecendo-se uma relação estrutura e atividade. Foram sintetizados 32 compostos através de reações de amidação entre uma lactona derivada do ácido quínico com diaminas Nalquiladas em rendimentos satisfatórios. 17 compostos apresentaram atividades semelhantes ou melhores do que a droga de referência. Também estão sendo realizados alguns ensaios antiparasitários e anti-inflamatórios com esses compostos. O terceiro capítulo descreve a síntese e avaliação das propriedades antitumorais de derivados de xantonas Garcinia, especificamente de cluvenona. Foram sintetizados diversos compostos com grupos retiradores e doadores de eletróns, hidrofílicos e contendo a unidade sal de trifenilfosfônio no anel A de hidroxicluvenonas, que auxiliarão no entendimento da relação estrutura e atividade para essa classe de compostos. Sintetizou-se também um composto derivado da 6- hidroxicluvenona condensada com o BODIPY com potencial atividade antitumoral e propriedades fluorescentes com o objetivo de realizar estudos de localização celular e mecanismo de ação. A etapa chave para a síntese desses compostos foi uma reação em cascata de Claisen/Diels-Alder. / In this work the synthesis and biological evaluation of different classes of organic compounds are described and it is divided into three chapters. The first chapter describes the synthesis of genistein derivatives with different physicochemical properties in order to assess the influence of these properties in biological activity against multiple sclerosis. Carbohydrate derivatives from D-glucose and D-galactose and compounds condensed with lipophilic alkyl or acyl linear chains of twelve or fourteen carbons were synthesized. Cytotoxicity and anti-inflammatory activities in vitro were performed and the most active compounds were evaluated in modulating the immune response in vivo model of experimental autoimmune encephalomyelitis. Reactivity of ethers derivatives was different: compounds with linear alkyl chains were obtained in higher yields, followed by the derivatives of D-glucose and D-galactose, respectively. The regioselectivity obtained in the synthesis of ether derivatives were suggested by nOe, while the ester derivatives were suggested by 1H NMR. All compounds showed in vitro activity and carbohydrate derivatives were more cytotoxic than lipophilic derivatives. After in vivo tests, compound 13 was considered a prototype for the treatment of multiple sclerosis. The second chapter describes the synthesis and evaluation of the antimicrobial properties of surfactants derived from quinic acid (popar part) condensates with N-alkylated diamines (nonpolar part). The size of the alkyl chain and the structure of quinic acid were altered, settling a relationship structure and activity. 32 compounds were synthesized by amidation reactions between a lactone derivative of quinic acid with N-alkylated diamines in satisfactory yields. 17 of these compounds showed equal or better equal activities than the drug reference. Some antiparasitic and anti-inflammatory tests are also being conducted for these compounds. The third chapter describes the synthesis and evaluation of antitumoral properties of derivatives of Garcinia xanthones, specifically cluvenone. Several compounds were synthesized with electron withdrawing and donors groups, containing hydrophilic and the triphenylphosphonium salt unit in the A ring of hidroxicluvenonas. These compounds will help in understanding the structure and activity relationship for this class of compounds. A BODIPY Hydroxicluvenone conjugate compound with potential antitumor activity and fluorescent properties was synthesized with the aim of studying the cellular location and mechanism of action. The key step for the synthesis of these compounds was a reaction cascade Claisen / Diels-Alder reaction.

Submitted by Renata Lopes (renatasil82@gmail.com) on 2017-05-04T12:42:14Z No. of bitstreams: 1 angelinamariadealmeida.pdf: 23133254 bytes, checksum: 7560d658fe12ed7f6166fc99ab314157 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2017-05-17T13:30:51Z (GMT) No. of bitstreams: 1 angelinamariadealmeida.pdf: 23133254 bytes, checksum: 7560d658fe12ed7f6166fc99ab314157 (MD5) / Made available in DSpace on 2017-05-17T13:30:51Z (GMT). No. of bitstreams: 1 angelinamariadealmeida.pdf: 23133254 bytes, checksum: 7560d658fe12ed7f6166fc99ab314157 (MD5) Previous issue date: 2016-07-29 / CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Os valores terapêuticos do ouro são conhecidos desde a China antiga e, atualmente, complexos de ouro são empregados no tratamento da artrite reumatóide. Outras propriedades biológicas relativas aos complexos de ouro(I) vêm sendo reportadas na literatura, como atividade antitumoral, antibacteriana, antiviral e antifúngica. A primeira parte dessa tese descreve a síntese de novos complexos lipofílicos de ouro(I) contendo núcleo 1,3,4-oxadiazol-2-tiona ou 1,3-tiazolidina-2-tiona, além de serem constituídos por fosfinas terciárias, como trifenilfosfina ou trietilfosfina. Após caracterização através de métodos espectroscópicos usuais (RMN de 1H, 13C, 31P, IV e EMAR), foram realizadas avaliações biológicas in vitro para todos os complexos de ouro(I) e seus respectivos ligantes orgânicos. Os resultados citotóxicos frente a linhagens tumorais (CT26WT e B16F10) e normais (BHK21) indicam acentuada atividade antitumoral devido aos baixos valores de IC50 quando comparados aos valores obtidos para os ligantes orgânicos e para a Cisplatina. A atividade antibacteriana dos complexos de ouro(I) contra as bactérias Gram-positivas Staphylococcus aureus e Staphylococcus epidermidis também mostrou-se satisfatória, uma vez que os complexos exibem baixos valores de CIM comparados aos resultados obtidos para os ligantes orgânicos e cloranfenicol. O desenvolvimento de metodologias de catálise por metais de transição, em especial o uso de paládio, tem atraído considerável atenção no meio acadêmico e industrial. Assim, a segunda parte do trabalho aborda o desenvolvimento de um método geral de preparação de ésteres ativos via alcoxicarbonilação catalisada por paládio e o acoplamento carbonilativo entre haletos de arila, cianato de potássio, álcoois e monóxido de carbono catalisada por paládio. Em ambos os casos, verifica-se a generalidade dos protocolos devido à diversidade e aos bons rendimentos do escopo obtido a partir de diferentes nucleófilos e haletos aromáticos e heteroaromáticos. / Therapeutic gold values are known since ancient China and gold complexes are currently employed in the treatment of rheumatoid arthritis. Other biological properties relative to the complexes of gold(I) have been reported in the literature, such as antitumor activity, antibacterial, antiviral and antifungal. The first part of this thesis describes the synthesis of novel lipophilic complexes of gold(I) containing core 1,3,4-oxadiazol-2-thione or 1,3-thiazolidine-2-thione, and they are constituted by tertiary phosphines, such as triphenylphosphine or triethylphosphine. After characterization using usual analythical methods (NMR 1H, 13C, 31P, IR and HRMS) the biological evaluations were performed in vitro for all complexes of gold(I) and their organic ligands. The cytotoxic results against tumor cells (CT26WT and B16F10) and normal cells (BHK21) show pronounced antitumor activity due to low IC50 values compared to the values obtained for the corresponding ligands and Cisplatin. The antibacterial activity for the complexes of gold(I) against Gram-positive bacteria Staphylococcus aureus and Staphylococcus epidermidis also proved to be satisfactory, since the complexes exhibit low MIC values compared to the results obtained for the ligands and chloramphenicol. The development of catalytic methodologies by transition metals, in particular the use of palladium, has attracted considerable attention in the academia and industry. Thus, the second chapter covers the development of a general method for preparation of active esters via palladium catalyzed alkoxycarbonilation and carbonilative coupling of aryl halides, potassium cyanate, alcohols and carbon monoxide. In both cases the generality of the protocols is confirmed by the diversity and good yields obtained to the scope from different nucleophiles and aromatic and heteroaromatic halides.

Please read the abstract in the section 00front of this document / Thesis (PhD)--University of Pretoria, 2010. / Immunology / unrestricted

Many previous studies have demonstrated that gold compounds possess successful results in catalysis and in medicinal chemistry. The central aim of this dissertation is the design and synthesis of novel gold (I) acyclic diamino carbene complexes as a chemotherapeutic agent for triple-negative breast cancer (TNBC) and for catalysis. In this study, a series of chiral neutral and cationic gold (I) acyclic diamino carbene (ADC) complexes and neutral gold (I) bis- ADC complexes have been synthesized. As the chiral neutral gold (I) ADCs, four diastereomers of S binaphthyl L proline tertiary butyl ester gold (I) chloride, S binaphthyl D proline tertiary butyl ester gold (I) chloride, R binaphthyl L proline tertiary butyl ester gold (I) chloride, and R binaphthyl D proline tertiary butyl ester gold (I) chloride have been synthesized and characterized. Different chiral gold (I) ADC complexes with bulky chiral binaphthyl group and with different amine groups of morpholine, chiral proline methyl ester, and benzyl ester have been synthesized and characterized. After that four diastereomers of the nitrile adduct of cationic binaphthyl proline tertiary butyl ester nitrile and four diastereomers of the isonitrile versions of it have been synthesized and characterized. A series of gold (I) cationic bis ADC complexes have been synthesized and characterized. All these novel gold ADC complexes were tested for biological activity against TNBC cell line MDA-MB-231 and cationic S binaphthyl D proline ester isonitrile adduct, S binaphthyl D proline ester isonitrile adduct and R binaphthyl D proline ester isonitrile adduct gave promising inhibition rates. According to Lipinski's rule, lipophilicity determines the effectiveness of the drug absorption to the body through the lipid membrane. To determine the drug-likeness of the gold ADC complexes, log P values were calculated for some of the synthesized complexes using a modified shake flask method. Gold (I) ADC complexes have been renowned for their ability in catalysis, but enantioselective catalysis is not that well studied. A3 coupling reaction is a well-known reaction for the synthesis of propargyl amines. Here, A3 coupling reaction with a chiral amine has been performed using the previously synthesized four diastereomers of binaphthyl proline tertial butyl ester gold (I) ADCs (SL, RD, RL, SD) as the catalyst expecting four different diastereomers of the product. The reaction exhibited reasonable yields but with a low enantiomeric excess (ee%). However, it gave proof of the principle that asymmetric induction is possible with the synthesized novel chiral gold (I) ADC complexes.

<p>Испитивано је хроматографско понашање (хроматографска липофилност) 29 стероидних једињења (триазола и тетразола, толуенсулфонилхидразида, диона, нитрила и динитрила) од потенцијалног биомедицинског значаја, испитивано је помоћу течне хроматографије високих перформанси на обрнутим фазама, применом две стационарне и две мобилне фазе. Липофилност, изражена преко ретенционог параметра logk, моделована је QSRR приступом. Формирани линеарни и нелинеарни модели омогућили су испитивање односа између ретенционих параметара и in silico молекулских дескриптора, који су израчунати на основу структуре испитиваних једињења. Добра предиктивна моћ формираних модела, добијених за калибрациони сет, потврђена је и применом екстерног тест сета и валидационог сета. Предиктивна моћ формираних модела потврђује могућност њиховог коришћења за предвиђање липофилности нових, структурно сличних, једињења. Примењене су и класификационе хемометријске методе (анализа главних компоненти и хијерархијска кластер анализа) како би се уочиле сличности и разлика између једињења. Поред тога, представљена је in vitro анализа антимикробног потенцијала испитиваних стероидних једињења према Staphylococcus aureus, Escherichia coli и Candida albicans. Два једињења, са епоксидном групом у положају 4,5, испољила су бактериостатски ефекат према S. aureus. Такође, приказана је докинг анализа одабраних испитиваних једињења са антипролиферативном активношћу према ћелијама андроген-рецептор негативног канцера простате (AR-нег. PC-3). На основу визуелизације оптималних положаја и анализе постојећих интеракција, идентификовано је једињење са највећим потенцијалом као инхибитор хуманог цитохрома P450 CYP17A1.</p> / <p>Ispitivano je hromatografsko ponašanje (hromatografska lipofilnost) 29 steroidnih jedinjenja (triazola i tetrazola, toluensulfonilhidrazida, diona, nitrila i dinitrila) od potencijalnog biomedicinskog značaja, ispitivano je pomoću tečne hromatografije visokih performansi na obrnutim fazama, primenom dve stacionarne i dve mobilne faze. Lipofilnost, izražena preko retencionog parametra logk, modelovana je QSRR pristupom. Formirani linearni i nelinearni modeli omogućili su ispitivanje odnosa između retencionih parametara i in silico molekulskih deskriptora, koji su izračunati na osnovu strukture ispitivanih jedinjenja. Dobra prediktivna moć formiranih modela, dobijenih za kalibracioni set, potvrđena je i primenom eksternog test seta i validacionog seta. Prediktivna moć formiranih modela potvrđuje mogućnost njihovog korišćenja za predviđanje lipofilnosti novih, strukturno sličnih, jedinjenja. Primenjene su i klasifikacione hemometrijske metode (analiza glavnih komponenti i hijerarhijska klaster analiza) kako bi se uočile sličnosti i razlika između jedinjenja. Pored toga, predstavljena je in vitro analiza antimikrobnog potencijala ispitivanih steroidnih jedinjenja prema Staphylococcus aureus, Escherichia coli i Candida albicans. Dva jedinjenja, sa epoksidnom grupom u položaju 4,5, ispoljila su bakteriostatski efekat prema S. aureus. Takođe, prikazana je doking analiza odabranih ispitivanih jedinjenja sa antiproliferativnom aktivnošću prema ćelijama androgen-receptor negativnog kancera prostate (AR-neg. PC-3). Na osnovu vizuelizacije optimalnih položaja i analize postojećih interakcija, identifikovano je jedinjenje sa najvećim potencijalom kao inhibitor humanog citohroma P450 CYP17A1.</p> / <p>Chromatographic behavior (chromatographic lipophilicity) of 29 steroid compounds (triazole and tetrazole, toluenesulfonylhydrazide, dione, dinitrile and nitrile) with potential biomedical importance was investigated by reversed-phases high-performance liquid chromatography using two stationary and two mobile phases. The lipophilicity expressed through the retention parameter logk was modeled using QSRR approach. Formed linear and non-linear models enabled the study of the relationship between the retention parameters and in silico molecular descriptors calculated from the structure of the investigated compounds. Good predictive power of the established models obtained for the calibration set was confirmed by the application of an external test set and validation set. The predictive power of the established model confirms the possibility of their use for lipophilicity prediction of new, structurally similar compounds. The classification chemometric methods (principal components analysis and hierarchical cluster analysis) were applied in order to recognize the similarities and differences between the compounds. Тhis dissertation presents the in vitro analysis of the antimicrobial potentials of the investigated steroid compounds against Staphylococcus aureus, Escherichia coli and Candida albicans. Two compounds, with epoxy group in the position 4,5, exhibited bacteriostatic effect against S. aureus. The docking analysis of selected test compounds with antiproliferative activity toward cells of androgen receptor-negative prostate cancer (AR-neg. PC-3) is showed. Based on the optimal position visualization and analysis of existing interactions a compound with the most promising potential as human cytochrome P450 CYP17A1 inhibitor is idetified.</p>