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Design and synthesis of new 6-nitro-4- piperazinylquinoline derivatives with antiproliferative effect on renal cancer cells
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Os rins são órgãos cruciais no corpo humano, desempenhando um papel vital na manutenção
da saúde geral e da homeostase. As doenças renais, em particular o Carcinoma de Células
Renais (RCC), representam uma ameaça significativa para a sobrevivência humana, sendo o
RCC um dos tipos mais prevalentes de cancro renal e responsável por milhares de mortes todos
os anos.
As opções de tratamento atuais atuam principalmente em vias de sinalização, sendo as terapias
centradas no fator de crescimento do endotélio vascular e no alvo da rapamicina em mamíferos
as primeiras intervenções disponibilizadas para os doentes com RCC. Apesar da disponibilidade
destes tratamentos, a taxa de mortalidade associada a esta neoplasia maligna permanece
alarmantemente elevada, sublinhando a necessidade urgente de desenvolvimento de novas
estratégias terapêuticas.
Em resposta a esta necessidade premente, a nossa investigação teve como objetivo sintetizar
um composto com quinolina com potenciais efeitos antiproliferativos contra o RCC. A estrutura
da quinolina é caracterizada como um sistema de anéis aromáticos deficientes em eletrões,
funcionando como uma base terciária fraca, que possibilita as reações eletrofílicas e
nucleofílicas. Este sistema é versátil e acessível, com as suas capacidades eletrónicas e estéricas
a permitem-lhe interagir com vários alvos biológicos implicados na progressão do cancro.
Vários derivados de quinolina foram já utilizados no tratamento do cancro, o que evidencia o
seu potencial terapêutico.
O processo de investigação desenrolou-se em três fases principais. Primeiro, realizámos uma
avaliação farmacocinética para avaliar as propriedades ADMET (Absorção, Distribuição,
Metabolismo, Excreção e Toxicidade) dos compostos que visámos sintetizar. De seguida,
procedemos a uma síntese em cinco etapas dos compostos-alvo. A fase final envolveu uma
avaliação biológica exaustiva dos produtos derivados da segunda etapa.
A síntese produziu múltiplos derivados de 4-(4-benzoilpiperazina-1-il)-6-nitroquinolina-3
carbonitrilo, que foram submetidos ao National Cancer Institute (NCI) nos Estados Unidos da
América para avaliação biológica. Os resultados desta avaliação desempenharão um papel
fundamental na orientação da nossa investigação. Se os resultados forem favoráveis, estes
novos derivados de quinolina poderão alterar significativamente o panorama do tratamento do
Carcinoma de Células Renais, salvando potencialmente inúmeras vidas no processo.
The kidneys are crucial organs in the human body, playing a vital role in maintaining overall health and homeostasis. Kidney diseases, particularly Renal Cell Carcinoma, represent a significant threat to human survival, with RCC being one of the most prevalent types of kidney cancer and responsible for thousands of deaths each year. Current treatment options primarily target signaling pathways, with therapies focusing on the vascular endothelial growth factor and the mammalian (or mechanistic) target of rapamycin being the earliest established interventions for RCC patients. Despite the availability of these treatments, the mortality rate associated with this malignancy remains alarmingly high, underscoring the urgent need for the development of novel therapeutic strategies. In response to this pressing need, our research aimed to synthesize a quinoline-based compound with potential antiproliferative effects against RCC. The quinoline structure is characterized as an electron-deficient aromatic ring system, functioning as a weak tertiary base, which facilitates both electrophilic and nucleophilic reactions. This system is versatile and accessible, with its’ electronic and steric abilities enabling it to interact with various biological targets implicated in cancer progression. Notably, several quinoline derivatives have already been employed in cancer treatment, highlighting their therapeutic potential. The research process unfolded in three principal phases. First, we conducted a pharmacokinetic assessment to evaluate the ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) properties of the compounds we aimed to synthesize. Following this, we undertook a five-step synthesis of the target compounds. The final phase involved a thorough biological evaluation of the products derived from the second step. The synthesis yielded multiple derivates of 4-(4-benzoylpiperazin-1-yl)-6-nitroquinoline-3 carbonitrile, which have been submitted to the National Cancer Institute (NCI) in the USA for biological evaluation. The outcomes of this assessment will play a critical role in guiding the direction of our research. Should the results be favorable, these novel quinoline derivatives could significantly alter the treatment landscape for Renal Cell Carcinoma, potentially saving countless lives in the process.
The kidneys are crucial organs in the human body, playing a vital role in maintaining overall health and homeostasis. Kidney diseases, particularly Renal Cell Carcinoma, represent a significant threat to human survival, with RCC being one of the most prevalent types of kidney cancer and responsible for thousands of deaths each year. Current treatment options primarily target signaling pathways, with therapies focusing on the vascular endothelial growth factor and the mammalian (or mechanistic) target of rapamycin being the earliest established interventions for RCC patients. Despite the availability of these treatments, the mortality rate associated with this malignancy remains alarmingly high, underscoring the urgent need for the development of novel therapeutic strategies. In response to this pressing need, our research aimed to synthesize a quinoline-based compound with potential antiproliferative effects against RCC. The quinoline structure is characterized as an electron-deficient aromatic ring system, functioning as a weak tertiary base, which facilitates both electrophilic and nucleophilic reactions. This system is versatile and accessible, with its’ electronic and steric abilities enabling it to interact with various biological targets implicated in cancer progression. Notably, several quinoline derivatives have already been employed in cancer treatment, highlighting their therapeutic potential. The research process unfolded in three principal phases. First, we conducted a pharmacokinetic assessment to evaluate the ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) properties of the compounds we aimed to synthesize. Following this, we undertook a five-step synthesis of the target compounds. The final phase involved a thorough biological evaluation of the products derived from the second step. The synthesis yielded multiple derivates of 4-(4-benzoylpiperazin-1-yl)-6-nitroquinoline-3 carbonitrile, which have been submitted to the National Cancer Institute (NCI) in the USA for biological evaluation. The outcomes of this assessment will play a critical role in guiding the direction of our research. Should the results be favorable, these novel quinoline derivatives could significantly alter the treatment landscape for Renal Cell Carcinoma, potentially saving countless lives in the process.
Descrição
Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, 2024, Universidade de Lisboa, Faculdade de Farmácia.
Palavras-chave
Renal cell carcinoma Quinoline derivates Oncology Mestrado Integrado - 2024