Thesis (Ph. D.)--Columbia University. / Biographical: 1 p. Bibliography: 1 p.

Thesis (Ph. D.)--Columbia University. / Biographical: 1 p. Bibliography: 1 p.

This thesis consists of two parts, both on synthetic chemistry with medicinal and biological relevance. Part one aims to develop methods for the preparation of quinazoline derivatives. A streamlined method for the preparation of 6-substituted-4-methyl-2-quinazolyl-guanidines and their respective amides has been presented here, using inexpensive and readily available starting materials such as para-bromoaniline, dicyandiamide (DCDA), and other reagents that are well-established for reactions such as Heck coupling, Suzuki coupling, and Ullman coupling reactions. In part two a novel methodology was developed for the specific incorporation of a masked N,O-acetal at the peptide bond between glycine and other amino acids including phenylalanine, alanine, valine, leucine, isoleucine, aspartate, glutamate, and the aromatic amino acids tyrosine and tryptophan. This methodology opens the door to linking a wide variety of derivatives, including carboxylic acids, to a specific peptide bond within a oligopeptide fragment. Such derivatives can be useful in the development of natural products containing these specific linkages or in the development of oligopeptides tagged at specific locations with a biodegradable and traceless linker useful in identifying and reacting with their peptide ligands.

Orientadores: Lilian Tereza Lavras Costallat, Kleber Gomes Franchini / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-13T01:28:13Z (GMT). No. of bitstreams: 1 Soledade_CiniraSantana_D.pdf: 1680992 bytes, checksum: 98f3f468653137a8796c59f9d6297f89 (MD5) Previous issue date: 2008 / Resumo: A inflamação é apontada como o principal processo mediador das diversas doenças do tecido conjuntivo e um componente importante da fisiopatologia das doenças infecciosas. Mais recentemente também tem lhe sido atribuído papel de destaque na obesidade, diabetes e doenças cardiovasculares, em especial a aterosclerose. Dentre os vários mediadores envolvidos no processo inflamatório, a adenosina tem sido apontada como um potente mediador endógeno. A adenosina é um autacóide, cuja ação se dá pela interação com quatro receptores de superfície celular (A1, A2A, A2B e A3), sendo a sua concentração modulada pelo equilíbrio entre os processos de síntese (5- nucleotidases), fosforilação (adenosina quinase), e deaminação (adenosina deaminase). A adenosina sabidamente age em múltiplos aspectos do processo inflamatório, como: apoptose, migração de leucócitos, liberação de mediadores (citocinas, quimiocinas) e mecanismos vasoregulatórios. No nível celular os efeitos da adenosina incluem várias vias de sinalização, modulando a ativação de importantes fatores de transcrição como o NF-?B. Neste contexto, a imunomodulação exercida pela adenosina tem seu potencial terapêutico reconhecido e avaliado na literatura, através do estudo de compostos que agem sobre seus receptores específicos ou através do aumento de sua concentração. O objetivo geral deste trabalho foi avaliar as propriedades antiinflamatórias e mecanismos de ação de um novo composto, inibidor de adenosina quinase (6,7-dimetóxi-4-N-(3'-N,N-dimetilfenil)aminoquinazolina, DMA), cuja ação resulta no aumento da concentração tecidual de adenosina. Para isso, foram utilizados modelos de inflamação aguda em animais de experimentação e ensaios in vitro em cultura de células. No modelo de peritonite aguda induzida por thioglicolato em camundongos, o tratamento com DMA reduziu o acúmulo de neutrófilos, (?55%, p < 0,05) e esse efeito foi bloqueado por um antagonista de receptor de adenosina, a 8-sulpho-phenil- theophilina. Ainda neste modelo, houve diminuição de Interleucina-6 no exudato dos animais tratados com DMA (?35%; p < 0,005). O DMA também foi efetivo na redução da inflamação nos modelos de artrite aguda em ratos, reduzindo o volume articular (?30% na segunda hora e ?35% na quarta hora; p < 0,05), número de leucócitos no líquido sinovial (?50% ; 28,6 x 106 ± 5,2 células/ml vs. 13,8 x 106 ± 1,7 células/ml; p < 0,05) e escala de dor (2,62 ± 0,18 vs. 1,53 ± 0,136; p < 0,05). No modelo de edema de pata induzidos por carragenina demonstrou-se uma redução do edema / Abstract: : Inflammation has a main role in several connective tissue diseases and is an important element of infectious disease physiopathology. Recently it has been linked to obesity, diabetes and cardiovascular diseases. Adenosine, among the various inflammatory process mediators, is a potent autocoid and its bioavailability is limited by catabolism to inosine by adenosine deaminase or by salvage following cellular uptake via adenosine kinase (ADK). Once in extracellular space adenosine interacts with specific cell-surface receptors (A1, A2, A2B, A3) and acts on multiples aspects of the inflammatory process: apoptosis, leukocyte migration, release of proinflammatory cytokines and vascular regulation. At cellular level adenosine acts in a wide-range of pathways, modulating important transcription factors like NF-?B. Based on these premises, adenosine immune regulatory properties and potential in therapeutics have been acknowledged and investigated through the study of specific receptors agonists and compounds able to increase its concentration. The main objective of this study was to evaluate the antiinflammatory properties and mechanisms of DMA, a novel adenosine kinase inhibitor, which increases adenosine tissue concentration. In order to accomplished that, animal models of acute inflammation and cell culture assay were used. DMA was orally effective to reduce neutrophils migration (~55%; p < 0,05) and IL-6 concentration (~35%; p < 0,005) in the aseptic thioglycollate peritonitis model. DMA significantly inhibited arthritis in an acute arthritis carrageenan model, decreasing articular volume (~30% second hour and ~35% fourth hour, p < 0,05), leukocytes on synovial liquid (~50% ; 28,6 x 106 ± 5,2 cells/ml vs. 13,8 x 106 ± 1,7 cells/ml; p < 0,05) and pain score (2,62 ± 0,18 vs. 1,53 ± 0,136; p <0 ,05). DMA was also effective in reducing edema in the carrageenan-induced paw edema model (~30% second hour and 36% fourth hour; p < 0,05) and pain in the second phase of the "Liking test" induced by formalin (~40% in liking time; p < 0,01). In vitro, macrophage expression of TLR4, an important cell receptor in recognizing and processing antigens, was decreased after DMA treatment. The results suggest that DMA also impacts the inflammatory cascade by modulating inflammatory related nuclear transcription. It was demonstrated that DMA was also able to inhibit macrophages and neutrophils, LPS induced NF-?B activation and promote PPAR activation in THP-1 cells. Antiinflammatories are drugs in high demand, but their use is still limited by side-effects. The DMA is a novel, potent non-nucleoside ADK inhibitor, orally effective to improve inflammation in some well characterized animal models and in vitro assays. New studies, based on this data, will be design to further explore the therapeutic use of DMA in inflammatory diseases / Doutorado / Ciencias Basicas / Doutor em Clínica Médica

Thesis (Ph.D. in Pharmaceutical Sciences) -- University of Colorado Denver, 2007. / Typescript. Includes bibliographical references (leaves 131-142). Free to UCD affiliates. Online version available via ProQuest Digital Dissertations;

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.

Orientadores: Nelci Fenalti Hoehr, Roberto Rittner / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-14T17:11:44Z (GMT). No. of bitstreams: 1 Oliveira_AndreNazariode_M.pdf: 1693019 bytes, checksum: c0e1f56be54157760e94e4822c8d9f5f (MD5) Previous issue date: 2009 / Resumo: Este projeto tem a finalidade de analisar as características toxicológicas de novos compostos quinazolínicos, que foram sintetizados recentemente no Instituto de Química-UNICAMP. Uma série de derivados de 4-fenilamino quinazolinas foi sintetizada como potentes inibidores da proteína quinase e sua citotoxicidade foi demonstrada através de técnicas de Inibição de Crescimento de 50% da população celular, onde procuramos estabelecer alguns efeitos biológicos desses novos compostos quinazolínicos, através de cultura de células PC12 e de cultura de células tumorais humanas, recomendadas pelo NCI (The U.S. National Cancer Institute) para ensaios anti-proliferiativos para estudos do câncer. A utilização da metodologia de "docking molecular" nos levou ao descobrimento do sítio de ação dos compostos quinazolínicos em células tumorais de mama (MCF07). Estudos com camundongos foram realizados, utilizando a metodologia recomendada pela OECD (Organisation for Economic Co-operation and Development), para determinação in vivo da toxicidade aguda pelos compostos quinazolínicos, descrevendo os efeitos causados pelas diferentes concentrações dos compostos quinazolínicos em estudo aplicadas aos animais. Através da Espectrometria de Ressonância Magnética Nuclear de Hidrogênio (¹H) pôde-se identificar o metabólito final das catecolaminas, o ácido homovanílico em urina, escolhido por ser um composto que aparece em grandes concentrações na urina e por ser de excelente precisão diagnóstica em algumas doenças neurológicas. / Abstract: This project aims to analyze the toxicological characteristics of new quinazoline compounds, which were summarized recently in the Institute of Chemistry-UNICAMP. The compound 4-phenylamino quinazoline was synthesized as a potent inhibitor of protein kinase and its cytotoxicity was demonstrated by an inhibitory activity on growth of human tumor cell lines. Through techniques of 50% Growth Inhibition of cell lines we provide some biological effects of these new quinazoline compounds through PC12 cell culture and culture of human tumor cells, as recommended by the NCI (The U.S. National Cancer Institute) for testing anti-proliferative for studies of cancer. The use of the methodology of "molecular docking" has led to the discovery the binding site of action of quianzoline compounds in breast tumor cells (MCF07). Studies with mice were performed, using the methodology recommended by the OECD (Organisation for Economic Co-operation and Development), to determine in vivo toxicity of the quinazoline compounds, describing the effects caused by different concentrations of quinazoline compounds under study applied to animals. Through the Nuclear Magnetic Resonance Spectrometry of Hydrogen (¹H) was able to identify the final metabolite of catecholamines, the acid in urine homovanílico, chosen to be a compound that appears in high concentrations in urine and to be an excellent diagnostic marker in some neurological diseases. / Mestrado / Ciencias Biomedicas / Mestre em Ciências Médicas

No description available.

Orientador : Kleber Gomes Franchini / Tese (Doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-22T00:30:15Z (GMT). No. of bitstreams: 1 Antunes_JoaoEustaquio_D.pdf: 5472161 bytes, checksum: d84f6389e6baf3e2959126f6345e6a14 (MD5) Previous issue date: 2013 / Resumo: A compreensão de como a quinase de adesão focal (FAK) contribui para os processos de hipertrofia, insuficiência cardíaca e câncer são de grande interesse científico. Um dos nossos objetivos específicos é desenvolver inibidores desta tirosina quinase com vistas à sua aplicação terapêutica no tratamento de insuficiência cardíaca e câncer. Portanto, foi realizado planejamento racional e a síntese de inibidores farmacológicos para a FAK. Estudos computacionais de docking e farmacocinéticos permitiram selecionar 28 estruturas de quinazolina mais promissoras em relação à capacidade de inibir a FAK. Desta forma, economiza-se tempo e dinheiro para obter-se a síntese apenas de 6 das estruturas pré-selecionadas. Uma quinazolina denominada 4-BZLO foi sintetizada após o planejamento racional. Tal quinazolina foi capaz de inibir em 50% da atividade da FAK in vitro com aproximadamente 1nM. Os testes de pureza da síntese, absorção por via oral, melhor resultado em triagem em células que superexpressam a FAK e o melhor resultado para triagem em duas linhagens de célula leucêmicas e tumor sólido permitiram direcionar o 4- BZLO para ser o composto líder deste estudo. O composto 4-BZLO apresentou resultado promissor para experimentos com camundongos submetidos à coarctação da aorta, que induz hipertrofia cardíaca. Para avaliar se o tratamento preventivo seria eficiente para hipertrofia cardíaca, foi realizado experimento em animais tratados com 30mg/Kg/dia durante 30 dias. Após este período, foi realizada cirurgia de coarctação da aorta para induzir a hipertrofia cardíaca nos animais e os mesmos foram tratados por mais 30 dias. Parâmetros tais como: peso médio do ventrículo esquerdo sobre peso corpóreo de cada animal (LVW/BW), medida da espessura da parede do ventrículo esquerdo (LVWT) e parâmetros histológicos (diâmetro dos miócitos cardíacos) demonstrou que nos animais tratados houve regressão da hipertrofia comparada ao controle (animais sem tratamento). Outro estudo realizado no qual os animais foram tratados de maneira curativa, ou seja, o tratamento foi realizado somente após a coarctação da aorta demonstrou uma melhora no quadro de hipertrofia e função cardíaca. O modelo de fibrose cardíaca foi usado para avaliar se tratamento com 4-BZLO é capaz de reduzir a fibrose cardíaca nos animais. Os resultados obtidos demonstraram que os animais tratados com 4-BZLO por 30 dias apresentaram redução da acumulação de colágeno, que é um indicador de fibrose, em relação ao controle. Nosso laboratório desenvolveu camundongos transgênicos específicos para a FAK que desenvolve moderada hipertrofia cardíaca. Assim, tal modelo permitiu testar o tratamento com o 4-BZLO para hipertrofia cardíaca induzida pela FAK. Os animais transgênicos específicos para a FAK foram tratados com o composto líder e houve melhora dos parâmetros cardíacos. Os resultados obtidos permitiram concluir que a quinazolina denominada 4-BZLO é um bom candidato a fármaco como inibidor da FAK / Abstract: Understanding how the focal adhesion kinase (FAK) contributes to the processes of hypertrophy, heart failure and cancer are of great scientific interest. One of our goals is to develop specific inhibitors of this tyrosine kinase with potential therapeutic application in the treatment of heart failure and cancer. In this view, we used rational design to select a group of possible FAK inhibitors. Computational studies such as docking and pharmacokinetic studies allowed us to select 28 structures most likely to inhibit FAK. In this way, we saved up time and money in devising the synthesis of 6 pre-selected structures. Accordingly, quinazoline 4-BZLO was prepared and was able to inhibit the in vitro activity of FAK by 50% at a concentration of approximately 1nM. Several factors contributed to 4-BZLO being chosen as the lead compound in this study: 1) the degree of purity achieved during synthesis; 2) good oral bioavailability; 3) the best inhibition values in cells over expressing FAK in screening, 4) the best result against two leukemic cell lines and one solid tumor target. 4-BZLO showed promising results in experiments with mice subjected to aortic coarctation, which develops cardiac hypertrophy. To assess whether 4- BZLO would be effective for the preventive treatment of cardiac hypertrophy, an experiment was conducted in animals treated with 30 mg/kg/day for 30 days. After this period, an aortic coarctation was performed surgically in order to induce cardiac hypertrophy in animals, and these were further treated for 30 days. Parameters such as left ventricular weight per body weight ratio (LVW/BW), measurement of the left ventricle wall thickness (LVWT), and histological parameters, such as the diameter of cardiac myocytes in treated animals showed that there was a regression of hypertrophy, compared to untreated animals (control). A similar study, where treatment with 4-BZLO was performed only after aortic coarctation showed an improvement regarding hypertrophy and cardiac function. A cardiac fibrosis model was used and the results obtained demonstrated that animals treated with 4-BZLO for 30 days showed a reduction of collagen accumulation, which is an indicator of fibrosis, equal to the control group. Our laboratory has developed transgenic mice specific for FAK, which develop moderate cardiac hypertrophy. Consequently, this model allows us to test 4-BZLO for the treatment of FAK induced cardiac hypertrophy. The transgenic animals were treated with 4-BZLO, leading to an improvement of the cardiac parameters. These results showed that synthetic quinazoline 4-BZLO is a good drug candidate for the inhibition of the FAK enzyme / Doutorado / Farmacologia / Doutor em Farmacologia

O tumor sob hipóxia apresenta resistência a terapia antitumoral convencional por diferentes mecanismos. O uso de métodos diagnósticos moleculares não invasivos, como imagem por PET, permite a identificação de tumores sob hipóxia e auxilia no delineamento da estratégia terapêutica mais adequada. Atualmente, diversas pesquisas têm demonstrado alternativas ao tratamento de tumores sob hipóxia, explorando características como, potencial redutor do tumor e inibição de mecanismos de adaptação celular para a sobrevivência sob essa condição. Assim, neste trabalho foi realizada a síntese e avaliação in vivo de novo derivado 2-nitroimidazol, contendo o grupo hidrofílico zwiteriônico amôniometil-trifluoroborato (AMBF3), 18F-AmBF3-bu-2NI, com potencial para geração de imagens de tumores sob hipóxia. O composto AmBF3-bu-2NI foi facilmente preparado em 4 etapas sintéticas. A marcação com 18F foi realizada via reação de troca isotópica 18F-19F e 18F-AmBF3-bu-2NI foi obtido em 14,8 ± 0,4% de rendimento radioquímico (n = 3) com decaimento corrigido, 24,5 ± 5,2 GBq/?mol de atividade específica e >99% de pureza radioquímica. Estudos de imagem e biodistribuição ex vivo em camundongos, portando tumores HT-29, demonstraram que 18F-AmBF3-bu-2NI possui rápido clearance do sangue, com excreção pelas vias hepatobiliar e renal. No entanto, o tumor não foi visualizado em imagens de PET até 3 h pós-injeção devido à baixa captação tumoral (0,54 ± 0,13 e 0,19 ± 0,04% AI/g em 1 e 3 h pós-injeção, respectivamente), devido à não difusão de 18F-AmBF3-bu-2NI através da membrana celular. Adicionalmente, compostos quinazolinicos com potencial aplicação em diagnóstico foram também sintetizados contendo unidades biorredutives, nitro-benzil e nitro-imidazol, além de grupo fluoroetil, inicialmente contendo 19F (frio), como padrão analítico para a síntese do radiotraçador. Entretanto, devido a formação de produtos voláteis durante a radiossíntese da unidade 2-[18F]fluoroetil 4-metilbenzenosulfonato (34*), para incorporação no anel quinazolínico, a obtenção do radiotraçador e os correspondentes estudos de biodistribuição e imagem não foram realizados. Em paralelo ao trabalho anterior, foi realizada a síntese de um conjunto de 12 compostos aminotriazolil-quinazolínicos com potencial atividade antitumoral, via reação de cicloadição CuAAC. Inicialmente todos derivados quinazolínicos obtidos no trabalho para aplicação no diagnóstico foram testados em uma série de linhagens de células tumorais sob condições de normóxia e hipóxia (MDA-MB-231, SKBR3, BT474, PC3, MKN45, U251, U87, MIA PaCa-2, Skmel37, e A549, na concentração de 10 ?M), empregando cisplatina como referência. Neste estudo, apenas os derivados contendo grupo nitro-benzil-triazólico 61 e 63, apresentaram cerca de 50% de inibição de células MKN45 em normóxia e 40% em células SKBR3 sob hipóxia, respectivamente. Na sequência, os 12 derivados aminotriazolil-quinazolínicos foram submetidos a avaliação da citotoxicidade in vitro sob as linhagens de células tumorais de mama (MDA-MB-231, SKBR3, BT474, na concentração de 30 ?M), empregado os controles positivos Erlotinib e ii Lapatinib. Apenas o derivado contendo a função ftalimida 9, não substituído nas posições C-6 e C-7 do anel quinazolínico, apresentou cerca de 60% de inibição de células SKBR3 em hipóxia. Paralelamente, os derivados aminotriazolil-quinazolínicos foram submetidos à avaliação de triagem da atividade inibitória frente as quinases HER2, EGFR e PERK, na concentração de 10 ?M. Todavia, não houve inibição significativa nas enzimas avaliadas na concentração testada. Novos ensaios estão em andamento a fim de determinar a capacidade dos compostos atuarem como inibidores do crescimento de outras linhagens de células tumorais. / Tumor hypoxia is resistant to conventional antitumor therapy by different mechanisms. The use of non-invasive molecular diagnostic methods, such as PET imaging, allows the identification of tumors under hypoxia and assists in designing the most appropriate therapeutic strategy. Currently, several researches have provided alternative treatments for tumors under hypoxia, exploring some specific properties, such as tumor reducing potential and inhibition of adaptive mechanisms required for cell survival under hypoxia. Thus in this work, it was performed the synthesis and in vivo evaluation of new 2-nitroimidazole derivative, containing the zwitterionic hydrophilic group, ammonium methyl- trifluoroborate (AMBF3), 18F-AmBF3-bu-2NI, with potential for tumor imaging in hypoxia. The compound AmBF3-bu-2NI was easily prepared in four steps. 18F labeling was conducted via 18F-19F isotope exchange reaction, and 18F-AmBF3-bu-2NI was obtained in 14.8 ± 0.4% (n = 3) decay-corrected radiochemical yield with 24.5 ± 5.2 GBq/?mol specific activity and > 99% radiochemical purity. Imaging and biodistribution ex vivo studies in HT-29 tumor-bearing mice showed that 18F-AmBF3-bu-2NI cleared quickly from blood, and was excreted via the hepatobiliary and renal pathways. However, tumor PET images were not visualized until 3 h post-injection due to low tumor uptake (0.54 ± 0.13 and 0.19 ± 0.04%ID/g at 1 h and 3 h post-injection, respectively) due to non-diffusion of 18F-AmBF3-bu-2NI through the cell membrane. Additionally, quinazolinic compounds with potential diagnostic application were also synthesized containing biorreductive units, nitrobenzyl and nitroimidazole, as well as a fluoroethyl group, initially containing 19F (cold), as an analytical standard for the synthesis of the radiotracer. However, due to the formation of volatile products during the radiosynthesis of the 2-[18F] fluoroethyl 4-methylbenzenesulfonate (34*) unit, for incorporation into the quinazoline ring, the radiotracer preparation and its corresponding biodistribution and imaging studies were not performed. Concomitantly to the previous work, the synthesis of a set of 12 aminotriazolyl-quinazoline compounds with potential antitumor activity was performed, via the CuAAC cycloaddition reaction. Initially, all quinazolinic derivatives obtained in the work for application in the diagnosis were tested in a range of tumor cell lines under normoxia and hypoxia conditions (MDA-MB-231, SKBR3, BT474, PC3, MKN45, U251, U87, MIA PaCa-2, Skmel37, and A549, at 10 ?M), using cisplatin as a reference. In this study, only the derivatives bearing the nitrobenzyltriazole group 61 and 63 showed about 50% inhibition of MKN45 cells in normoxia and 40% in SKBR3 cells under hypoxia, respectively. In the sequence, the 12 aminotriazolyl-quinazoline derivatives were submitted to in vitro cytotoxicity evaluation using breast tumor cell lines (MDA-MB-231, SKBR3, BT474, at 30 ?M), in the presence of the reference drugs Erlotinib and Lapatinib. Only the derivative containing the phthalimide function 9, unsubstituted at C-6 and C-7 positions of the quinazoline ring, displayed about 60% inhibition on SKBR3 cells under hypoxia. Concomitantly, the inhibitory iv activity of these aminotriazolyl-quinazoline derivatives were also subjected to a screening evaluation against the HER2, EGFR and PERK kinases, 10 ?M. However, there was no significant inhibition of these enzymes at the tested concentration. New assays are ongoing to determine the inhibitory activity under other tumor cell lines.