Síntese e avaliação fotocitotoxicológica de corantes esquarílicos
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2019-07-29
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Atualmente, uma das principais causas de morte são as doenças de foro oncológico. A terapia fotodinâmica (PDT) surge como uma necessidade de explorar terapias alternativas devido aos efeitos secundários que estão implícitos nas terapias convencionais. Esta técnica terapêutica consegue provocar citotoxicidade nas células tumorais poupando ao mesmo tempo o tecido saudável. Isto acontece devido a uma tríade de componentes, fotossensibilizador (FS), oxigénio e luz por si só inofensivos, mas quando juntos capazes de iniciar uma reação fotoquímica que culmina na produção de agentes tóxicos letais, principalmente oxigénio singuleto ( 1O2), que acabam por induzir a morte celular. A escolha do agente FS é extremamente importante para o sucesso da PDT e a classe dos corantes cianínicos tem-se vindo a mostrar bastante interessante devidos às características que lhe estão inerentes. O principal objetivo do presente trabalho foi o desenvolvimento de novos corantes cianínicos aminoesquarílicos com forte absorção no infravermelho próximo, boa permeabilidade celular e ainda elevada seletividade para as células tumorais de forma a otimizar o seu potencial como agentes FS. Para tal, começou-se por sintetizar vários corantes aminoesquarílicos com grupos terminais derivados do 2-metilbenzotiazole e 2-metilquinolina adequadamente funcionalizados na parte amina com elementos de reconhecimento celular. Os novos corantes sintetizados foram caracterizados estruturalmente por espectroscopia UV/Vis, IV, 1H-RMN, 13C-RMN e massa exata. Seguindo-se a avaliação da capacidade de geração de 1O2 e por fim da sua (foto)citotoxicidade in vitro tanto dos corantes funcionalizados como dos seus percursores. Relativamente à síntese, enquanto que a funcionalização com colesterol se mostrou eficiente já a funcionalização com glucose não foi possível. Em relação à capacidade de produção de 1O2 esta mostrou-se mais eficiente nos corantes halogenados com iodo. Os resultados experimentais obtidos in vitro indicam que, considerando apenas as linhas celulares tumorais, os corantes aminoesquarílicos não funcionalizados com o colesterol mostram ser mais eficientes. Contudo, os seus análogos funcionalizados mostram ser melhores FS quando se comparam os valores das linhas celulares tumorais com a linha não tumoral (PLP2), uma vez que estes mostramse menos fotocitotóxicos na linha não tumoral.
Currently, one of the main causes of death are cancer diseases. Photodynamic therapy (PDT) arises as a need to explore alternative therapies because of the side effects that are implicit in conventional therapies. This therapeutic technique can cause cytotoxicity in tumor cells while sparing healthy tissue. This happens due to a triad of components, photosensitizer (FS), oxygen and light by themselves harmless, but when together able to initiate a photochemical reaction that culminates in the production of toxic lethal agents, mainly singlet oxygen ( 1O2), that end up inducing cell death. The choice of the FS agent is extremely important for the success of PDT and the class of cyanine dyes has been very interesting due to its inherent characteristics. The main objective of the present work was the development of new aminosquaraines cyanine dyes with strong absorption in the near infrared, good cellular permeability and still high selectivity for tumor cells in order to optimize their potential as FS agents. To this end, several aminosquaraines dyes with terminal groups derived from 2-methylbenzothiazole and 2- methylquinoline were suitably functionalized on the amine part with cell recognition elements. The new synthesized dyes were structurally characterized by UV/Vis spectroscopy, IR, 1H-NMR, 13CNMR and exact mass. Followed by the evaluation of the generation capacity of 1O2 and the end of its in vitro (photo) cytotoxicity of both functionalized dyes and their precursors. Regarding the synthesis, while functionalization with cholesterol proved to be efficient, functionalization with glucose was not possible. In relation to the 1O2 production capacity, it has been shown to be more efficient in halogenated iodine dyes. The experimental results obtained in vitro indicate that, considering only the tumor cell lines, the non-functionalized aminosquaraines dyes with cholesterol show to be more efficient. However, their functionalized analogues show to be better FS when comparing the values of the tumor cell lines with the non-tumor line (PLP2), since these are shown to be less photocytotoxic in the non-tumor line.
Currently, one of the main causes of death are cancer diseases. Photodynamic therapy (PDT) arises as a need to explore alternative therapies because of the side effects that are implicit in conventional therapies. This therapeutic technique can cause cytotoxicity in tumor cells while sparing healthy tissue. This happens due to a triad of components, photosensitizer (FS), oxygen and light by themselves harmless, but when together able to initiate a photochemical reaction that culminates in the production of toxic lethal agents, mainly singlet oxygen ( 1O2), that end up inducing cell death. The choice of the FS agent is extremely important for the success of PDT and the class of cyanine dyes has been very interesting due to its inherent characteristics. The main objective of the present work was the development of new aminosquaraines cyanine dyes with strong absorption in the near infrared, good cellular permeability and still high selectivity for tumor cells in order to optimize their potential as FS agents. To this end, several aminosquaraines dyes with terminal groups derived from 2-methylbenzothiazole and 2- methylquinoline were suitably functionalized on the amine part with cell recognition elements. The new synthesized dyes were structurally characterized by UV/Vis spectroscopy, IR, 1H-NMR, 13CNMR and exact mass. Followed by the evaluation of the generation capacity of 1O2 and the end of its in vitro (photo) cytotoxicity of both functionalized dyes and their precursors. Regarding the synthesis, while functionalization with cholesterol proved to be efficient, functionalization with glucose was not possible. In relation to the 1O2 production capacity, it has been shown to be more efficient in halogenated iodine dyes. The experimental results obtained in vitro indicate that, considering only the tumor cell lines, the non-functionalized aminosquaraines dyes with cholesterol show to be more efficient. However, their functionalized analogues show to be better FS when comparing the values of the tumor cell lines with the non-tumor line (PLP2), since these are shown to be less photocytotoxic in the non-tumor line.
Descrição
Dissertação de Mestrado em Bioquímica
Palavras-chave
terapia fotodinâmica , fotossensibilizador