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Triazenes, compounds containing a diazoamino moiety (–N(1)=N(2)–N(3)<), are known for their reversible cis-trans isomerization character and hence, have the potential to be used in photoswitchable devices and photostorage media. However, little is known about their cis-trans isomerization mechanism. In this thesis, kinetic studies on the thermal cis-to-trans isomerization of N-(phenylazo)-substituted nitrogen heterocycles are presented. It is shown that the isomerization rate constant increases as the size and electron-donating character of the cyclic amine increases, as the electron-withdrawing character of the para substituent group on the phenyl ring increases, and as the polarity of the solvent increases. All these trends are interpreted in terms of a rotational isomerization mechanism involving a dipolar transition state. In addition, photolytic cleavage of the N(2)–N(3) bond of target substrates is shown to be affected as well by the size and electronic character of the cyclic amine, the electronic character of the phenyl ring substituent, and the polarity of the solvent, with the result that the photolysis yield increases as the isomerization rate decreases. Theoretical calculations on target substrates both in the gas phase and various solvents were also performed based on DFT-B3LYP/6-31+G* method. Overall, the cis-to-trans isomerization is predicted to take place through rotation around the N(1)=N(2) bond. Furthermore, the calculated energy barriers are found to be influenced by the size and electronic character of the cyclic amine, the electronic character of the phenyl ring substituent, and the polarity of the solvent, consistent with the effects obtained experimentally from the kinetic studies.

Triazenes, compounds containing a diazoamino moiety (–N(1)=N(2)–N(3)<), are known for their reversible cis-trans isomerization character and hence, have the potential to be used in photoswitchable devices and photostorage media. However, little is known about their cis-trans isomerization mechanism. In this thesis, kinetic studies on the thermal cis-to-trans isomerization of N-(phenylazo)-substituted nitrogen heterocycles are presented. It is shown that the isomerization rate constant increases as the size and electron-donating character of the cyclic amine increases, as the electron-withdrawing character of the para substituent group on the phenyl ring increases, and as the polarity of the solvent increases. All these trends are interpreted in terms of a rotational isomerization mechanism involving a dipolar transition state. In addition, photolytic cleavage of the N(2)–N(3) bond of target substrates is shown to be affected as well by the size and electronic character of the cyclic amine, the electronic character of the phenyl ring substituent, and the polarity of the solvent, with the result that the photolysis yield increases as the isomerization rate decreases. Theoretical calculations on target substrates both in the gas phase and various solvents were also performed based on DFT-B3LYP/6-31+G* method. Overall, the cis-to-trans isomerization is predicted to take place through rotation around the N(1)=N(2) bond. Furthermore, the calculated energy barriers are found to be influenced by the size and electronic character of the cyclic amine, the electronic character of the phenyl ring substituent, and the polarity of the solvent, consistent with the effects obtained experimentally from the kinetic studies.

Nesta tese foi desenvolvida uma nova classe de porfirinas supramoleculares contendo um grupo (4-nitrofenil)triazeno ligado na posição meso-aril do anel porfirínico. Suas propriedades estruturais e eletrônicas foram investigadas por espectrometria de massas, espectroscopia eletrônica de absorção e emissão, cálculos teóricos semi-empíricos, ressonância magnética nuclear de 1H e 13C, voltametria cíclica e espectroeletroquímica. Efeitos eletrônicos e estruturais diferenciados foram observados quando o grupo triazeno é inserido na porfirina, fazendo com que estes novos compostos apresentem novas propriedades quanto, por exemplo, às fragmentações no estado gasoso, deslocamento batocrômico nos espectros eletrônicos de absorção, variação das intensidades relativas e nos valores dos rendimentos quânticos de fluorescência, deslocalização eletrônica nos orbitais de fronteira evidenciando as transições de transferência de carga do ânion triazenido para o anel porfirínico e variações nos processos redox dos compostos até então estudados / In this thesis we has been developed a new class of supramolecular porphyrins containing (4-nitrophenyl)triazene group connected in the meso-aryl-position of the porphyrin ring. Their structural and electronic properties were investigated by mass spectrometry, absorption and emission electronic spectroscopy, semi-empirical theoretical calculations, nuclear magnetic resonance of 1H and 13C-NMR, cyclic voltammetry and spectroelectrochemistry. Different structural and electronic effects were observed when the unit is inserted into the triazene to porphyrin, so that these presents new properties such as, for example, to fragmentation in the gaseous state, bathocrimic shift in the electronic absorption spectra, relative intensity variation and values the fluorescence quantum yields, electron delocalization in the frontier orbitals showing the charge-transfer transitions from the triazenide anion to the porphyrin ring and changes in redox processes of compounds previously studied.

Nesta tese foi desenvolvida uma nova classe de porfirinas supramoleculares contendo um grupo (4-nitrofenil)triazeno ligado na posição meso-aril do anel porfirínico. Suas propriedades estruturais e eletrônicas foram investigadas por espectrometria de massas, espectroscopia eletrônica de absorção e emissão, cálculos teóricos semi-empíricos, ressonância magnética nuclear de 1H e 13C, voltametria cíclica e espectroeletroquímica. Efeitos eletrônicos e estruturais diferenciados foram observados quando o grupo triazeno é inserido na porfirina, fazendo com que estes novos compostos apresentem novas propriedades quanto, por exemplo, às fragmentações no estado gasoso, deslocamento batocrômico nos espectros eletrônicos de absorção, variação das intensidades relativas e nos valores dos rendimentos quânticos de fluorescência, deslocalização eletrônica nos orbitais de fronteira evidenciando as transições de transferência de carga do ânion triazenido para o anel porfirínico e variações nos processos redox dos compostos até então estudados / In this thesis we has been developed a new class of supramolecular porphyrins containing (4-nitrophenyl)triazene group connected in the meso-aryl-position of the porphyrin ring. Their structural and electronic properties were investigated by mass spectrometry, absorption and emission electronic spectroscopy, semi-empirical theoretical calculations, nuclear magnetic resonance of 1H and 13C-NMR, cyclic voltammetry and spectroelectrochemistry. Different structural and electronic effects were observed when the unit is inserted into the triazene to porphyrin, so that these presents new properties such as, for example, to fragmentation in the gaseous state, bathocrimic shift in the electronic absorption spectra, relative intensity variation and values the fluorescence quantum yields, electron delocalization in the frontier orbitals showing the charge-transfer transitions from the triazenide anion to the porphyrin ring and changes in redox processes of compounds previously studied.

Overexpression of the epidermal growth factor receptor (EGFR), a member of the ErbB family, and its closest homologue HER2, have been associated with aggressive tumour progression and reduced sensitivity to DNA-damaging agents. In order to block the proliferation of refractory tumors overexpressing EGFR, a novel strategy has been developed that sought to design molecules capable of not only blocking EGFR-TK, but also damaging DNA. These molecules, termed combi-molecules (CMs), have been shown to degrade under physical conditions to release another inhibitor of EGFR, and to be potent against tumor cells of various origins including breast, prostate and carcinoma of the vulva. However, despite their potency, their growth inhibitory IC50 values were still in the high micromolar range. In order to augment the potency of the CMs, here they were re-designed to contain two quinazoline moieties and a central N,N-bis(2-aminoethyl)methylamine spacer which, following degradation, could yield higher concentrations of free inhibitors and a more cytotoxic bifunctional DNA damaging species. Here, we describe the mechanism of action of the first prototype of this approach, JDE52, which we now classify as a double-arm CM, in comparison with ZRBA1, its closest single-arm counterpart. The results indicated that JDE52 was capable of inducing significant blockade of EGFR, DNA single-strand breaks and inter-strand cross-links. ZRBA1, its single-arm counterpart, was capable of only forming DNA single-strand breaks. The fluorescent property of FD105, the secondary inhibitor that both JDE52 and ZRBA1 are capable of releasing, has permitted the analysis of its levels in tumor cells by UV flowcytometry. It was found that JDE52 was indeed capable of significantly releasing higher levels of fluorescence (p&lt;0.05) in human tumor cells, compared with levels of fluorescence released by ZRBA1. More importantly, JDE52 induced higher levels of apoptosis and cell killing than ZRBA1. Apoptosis was triggered by JDE52 at a faster rate than ZRBA1. The results in toto suggest that the superior potency of JDE52, when compared with ZRBA1, may be imputed to mechanisms associated with the generation of higher levels of FD105 intracellularly, and the induction of DNA cross-links, which are known to be more cytotoxic. These combined mechanisms (blockade of EGFR-TK and formation of cross-links) contributed to an accelerated rate of apoptosis in cells treated with JDE52. This study conclusively demonstrated that designing molecules as prodrugs of high levels of quinazoline inhibitors of EGFR and bifunctional DNA cross-linking species is a valid strategy to enhance the potency of CMs against refractory tumors.

Conselho Nacional de Desenvolvimento Científico e Tecnológico / The Triazenes are compounds with proven antibacterial and cytotoxic activity. Variations in the chemical structure such as complexation with metals like gold (I) can confer different biological activities. The antineoplastic temozolomide and dacarbazine are examples of commercially available triazenes used in the treatment of solid tumors and acute leukemias. In this study, the following compounds were synthesized triazenes complexed with novel gold (I): 1) [1,3-Bis (2-fluorophenyl) triazenido] (triphenylphosphine) gold (I); 2) [1,3-Bis (2- chlorophenyl) triazenido] (triphenylphosphine) gold (I) 3) [1,3-Bis (2-bromophenyl) triazenido] (triphenylphosphine) gold (I), 4) [1,3-Bis (2-iodophenyl) triazenido] (triphenylphosphine ) gold (I). Cytotoxicity of these compounds was evaluated by the MTT colorimetric assay of cell culture effecting bone marrow of patients with different types of leukemia, in addition to controlling patient without the disease. For the analysis of the antimicrobial activity was utilized quantitative methodology of microdilution with the determination of minimum inhibitory concentration (MIC). To determine the activity of nuclease cleavage assays were performed in double-stranded plasmid DNA using the method of electrophoresis in agarose gel. The results showed a considerable activity against different types of leukemia (acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia) with a small IC50 value of 0.0057 μmol mL-1 for compound 4 in cells of acute myeloid leukemia, all the active compounds in different types of leukemia but not so selective. The antibacterial activity was higher against gram-positive bacteria mainly in different strains of Staphylococcus aureus (MIC value of equal to 16 ug/ml). Any of the four compounds analyzed in this study was able to cleave the plasmid DNA. Thus, all tested triazenes have biological potential, or may be the subject of further studies as alternatives to anticancer and antimicrobial drugs existent. / Os triazenos são compostos com comprovada atividade citotóxica e antibacteriana. Variações na sua estrutura química, como por exemplo a complexação com metais como o ouro (I), podem lhe conferir diferenciadas atividades biológicas. Os antineoplásicos dacarbazina e temozolomida constituem exemplos de triazenos disponíveis comercialmente utilizados no tratamento de tumores sólidos e leucemias agudas. Neste estudo foram sintetizados os seguintes compostos triazenos inéditos complexados com ouro (I): 1) [1,3- Bis(2-fluorofenil)triazenido](trifenilfosfina)ouro(I); 2) [1,3-Bis(2 clorofenil)triazenido] (trifenilfosfina)ouro(I); 3) [1,3-Bis(2-bromofenil)triazenido](trifenilfosfina)ouro(I); 4) [1,3- Bis(2 iodofenil)triazenido](trifenilfosfina)ouro(I). A citotoxicidade desses compostos foi avaliada através do ensaio colorimétrico do MTT efetuando cultura de células de medula óssea de pacientes com diferentes tipos de leucemias, além de paciente controle, sem a doença. Para a análise da atividade antimicrobiana foi utilizada a metodologia quantitativa da microdiluição em caldo com a determinação da concentração inibitória mínima (CIM). Para a determinação da atividade de nuclease foram efetuados ensaios de clivagem do DNA plasmidial fita dupla utilizando a metodologia de eletroforese em gel de agarose. Os resultados mostraram uma considerável atividade frente a diferentes tipos de leucemias (leucemia mielóide aguda, leucemia mielóide crônica, leucemia linfóide aguda, leucemia linfóide crônica) com um pequeno valor de IC50 de 0,0057 μmol mL-1 para o composto 4 em células de leucemia mielóide aguda, sendo todos os compostos ativos em diferentes tipos de leucemias, porém de forma não seletiva. A maior atividade antibacteriana foi frente a bactérias gram-positivas principalmente em diferentes cepas de Staphylococcus aureus (com valor de CIM igual a 16 ug/mL). Nenhum dos 4 compostos analisados nesse estudo conseguiu clivar o DNA plasmidial. Desta forma, todos os triazenos testados possuem potencial biológico, ou seja, podem ser objeto de mais estudos como alternativas aos fármacos antimicrobianos e antineoplásicos existentes.

Cancer represents one of the leading causes of death worldwide and efforts to discover more effective anticancer therapies have led to the synthesis of a wide diversity of molecular species. Another major challenge is the anti-infective treatment, because despite the large arsenal of active substances available, many show inefficiency due to the rapid emergence of resistant bacterial strains. As a result, arises the necessity of finding new active substances, more effective and targeted properties in both treatments of neoplasms as microbial resistance. Notably, the Triazenes compounds (TZCs) have been asserting itself as a promising class of metallodrugs with relevant antimicrobial and antiproliferative activity. Moreover, the association of pharmacophoric radical TZC with metal ions, such as gold, leads to a significant increase in biological activity. Because of this wide pharmacological versatility, this study aimed the evaluating in vitro of the biological activity of a compound TZC complexed with ion gold (I). The antibacterial activity was carried out by the conventional method of broth microdilution, through the technique of the minimum inhibitory concentration (MIC), against bacterial strains reference standard American Type Culture Collection (ATCC), clinical isolates with multidrug resistance (MDR) and clinical isolates biofilm producers. Cytotoxicity was evaluated by colorimetric assay based on the reduction of bromide of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) (MTT) against the standard cell line K562 (Chronic Myeloid Leukemia). The results obtained demonstrate that the compound in study present a narrow spectrum of action, being active only against microorganisms classified as Gram positive, moreover, proved to be active against all isolates producing biofilm when compared to non-producing strains of biofilm. Also showed remarkable cytotoxic activity, with IC50 4.96 μM. Thus, these results demonstrate an alternative to the design of a new class of antibacterial and antitumor metallodrugs with activity. / O câncer representa uma das principais causas de óbito no mundo e esforços para descobrir terapias antineoplásicas mais eficazes têm conduzido à síntese de inúmeras moléculas. Outro grande desafio é o tratamento anti-infeccioso, pois apesar do grande arsenal de substâncias ativas disponíveis, muitas mostram-se ineficazes devido ao rápido aparecimento de estirpes bacterianas resistentes. Em razão disso, surge a necessidade da descoberta de novas substâncias ativas, com propriedades mais eficazes e direcionadas, tanto nos tratamentos de neoplasias como de resistência microbiana. Notoriamente, os compostos Triazenos (TZCs) vêm afirmando-se como uma classe promissora de metalofármacos com relevante atividade antimicrobiana e antiproliferativa. Além disso, a associação do radical farmacofórico TZC com íons metálicos, como o ouro, leva a um aumento significativo na atividade biológica. Em virtude dessa ampla versatilidade farmacológica, este estudo teve como objetivo a avaliação in vitro da atividade biológica de um composto TZC complexados com íon ouro (I). A atividade antibacteriana foi realizada pelo método convencional da microdiluição em caldo, através da técnica da concentração inibitória mínima (CIM), frente às cepas bacterianas padrão de referência American Type Culture Collection (ATCC), isolados clínicos com resistência a múltiplas drogas (RMD) e isolados clínicos produtores de biofilme. A citotoxicidade foi analisada através do ensaio colorimétrico baseado na redução do brometo de 3-(4,5-dimetiltiazol-2-il)-2,5 difeniltetrazólio) (MTT), frente às células da linhagem padrão K562 (Leucemia Mieloide Crônica). Os resultados obtidos demonstram que o composto em estudo apresentou estreito espectro de ação, sendo ativo somente frente aos microrganismos classificados como Gram positivos, além disso, mostrou-se ativo frente a todos os isolados produtores de biofilme, quando comparado às cepas não produtoras de biofilme. Também demonstrou notável atividade citotóxica, tendo a IC50 4.96 μM. Sendo assim, esses resultados demonstram uma alternativa para a concepção de uma nova classe de metalofármacos com atividade antibacteriana e antitumoral.

Leukemias are a heterogeneous group of hematologic malignancies. The treatment of these neoplasms has been a challenge to the scientific community due to genetic diversity in leukemic cells. Acquired chromosomal abnormalities as well as modifications of gene expression are involved in the genesis of leukemia. Such facts have increased interest in the development of new effective chemotherapeutic agents that reach specific molecular targets. The compounds of the triazene class like dacarbazine and temozolomide have been used in the clinical treatment of various cancer types, including melanoma, leukemia and glioma. Two new compounds triazenes complexed with copper (CuII) were synthesized to identify new agents with antiproliferative and antibacterial activity. The Compounds 1 - Bis [ 1,3-bis (2-chlorofenyl) triazenido-N11,N13--O-methoxy-pyridine-N-copper(II)] - C36H34N8O2Cl4Cu2 and 2 - Bis [1,3-bis (2-fluorfenyl) triazenido-N11,N13--O-hidroxy-pyridine-N-copper(II)]-C34H28N8O2F4Cu2 were tested in leukaemic cells from AML, ALL, CML and MDS in vitro by MTT colorimetric assay. A higher-capacity of antiproliferative was verified in compound 1 with cytotoxicity (IC50: 3.8 to 28.6 μM) in most cell types at diagnosis, particularly in cells with chromosome abnormalities. This compound also showed in vitro cytotoxicity of relapse of ALL cells with karyotypic alterations. The cytotoxic activity was significantly higher in leukemic cells than in normal cells. The MIC values showed that compound 1 had higher activity than compound 2, showing narrow spectrum antibacterial activity against gram positive ATCCs and multiresistant bacterial strains. It was observed that Compound 1 was more promising in relation to the antiproliferative potential than the antimicrobial activity, even when compared to antineoplastic agents such as etoposide. Additional studies to understand the mechanism of action will soon be developed. / As leucemias formam um grupo heterogêneo de neoplasias hematológicas. O tratamento destas neoplasias vem sendo um desafio à comunidade científica devido à diversidade genética nas células leucêmicas. Alterações cromossômicas adquiridas e modificações da expressão gênica estão envolvidas na gênese das leucemias. Isto tem estimulado o interesse no desenvolvimento de novos agentes quimioterapêuticos eficazes que atinjam alvos moleculares específicos. Os compostos da classe triazeno, tais como a dacarbazina e temozolomida, têm sido usados no tratamento clínico de diversos tipos de câncer, incluindo glioma, leucemia e melanoma. Dois novos compostos triazenos complexados com cobre (CuII) foram sintetizados com o objetivo de identificar novos agentes com atividade antiproliferativa e antibacteriana. Os compostos 1 - Bis[1,3-bis(2-clorofenil)triazenido-N11,N13--O-metóxi-piridina-N-cobre(II)] - C36H34N8O3Cl4Cu2 e 2- Bis[1,3-bis(2-fluorfenil)triazenido-N11,N13--O-hidróxi-piridina-N-cobre(II)] - C36H34N8O3F4Cu2 foram testados em células leucêmicas de LMA, LLA, LMC e SMD in vitro pelo teste colorimétrico MTT. O composto 1 apresentou melhor atividade citotóxica frente à maioria dos tipos celulares avaliados neste estudo (IC50: de 3,8 a 28,6 μM) especialmente em células com alterações cromossômicas. Este composto ainda apresentou citotoxicidade em células de recidiva de LLA com alterações cariotípicas. Ressaltamos que sua atividade citotóxica foi significativamente mais elevada em células leucêmicas do que em células normais. Os valores de CIM demonstraram que o composto 1 apresentou maior atividade antibacteriana que o composto 2, apresentando atividade de estreito espectro frente a cepas bacterianas gram positivas ATCCs e multirresistentes. Observou-se que o composto 1 foi mais promissor em relação ao potencial antiproliferativo do que ao potencial antibacteriano, inclusive quando comparado a agentes antineoplásicos como o etoposide. Estudos adicionais para melhor compreensão do mecanismo de ação deverão ser desenvolvidos.