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Topoisomerases do tipo II como alvos terapĂȘuticos para a terapĂȘutica anticancerĂgena
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Abstract(s)
As neoplasias estĂŁo entre as principais causas de morte do sĂ©culo XXI e caracterizam-se pelo aparecimento de cĂ©lulas que crescem de forma descontrolada e indefinida. O risco de desenvolvimento de neoplasia, seja qual for a sua localização, aumenta na presença de fatores tais como a imunosupressĂŁo, que pode estar relacionada com o stress, com a idade e/ou com a administração de determinados fĂĄrmacos, sendo exemplo disso os corticosteroides, antibacterianos, entre outros. O desenvolvimento de fĂĄrmacos antineoplĂĄsicos seletivos e seguros permanece um dos maiores desafios da QuĂmica FarmacĂȘutica. As topoisomerases de ADN sĂŁo enzimas nucleares ubĂquas envolvidas nos processos de regulação do estado topolĂłgico do ADN, que apresentam um aumento da sua atividade em vĂĄrios tipos de cancro, podendo mesmo funcionar como biomarcadores. Desta forma, as topoisomerases sĂŁo consideradas alvos terapĂȘuticos para a terapia anticancerĂgena, sendo de especial interesse o desenvolvimento de inibidores de topoisomerases que possam ser utilizados. Os inibidores das topoisomerases, nomeadamente os do tipo II, sĂŁo utilizados para o tratamento de vĂĄrios tipos de cancro e podem ser divididos, de acordo com o seu mecanismo de ação, em venenos de topoisomerases, como a doxorrubicina e o etopĂłsido, e em inibidores catalĂticos, como a merbarona. Contudo, apesar de serem amplamente prescritos, estes fĂĄrmacos estĂŁo associados Ă possibilidade de desenvolvimento de efeitos colaterais graves, como cardiotoxicidade e neoplasia secundĂĄria iatrogĂ©nica, levando ainda ao desenvolvimento de resistĂȘncias. Estas limitaçÔes suscitam a necessidade de desenvolver novas estratĂ©gias que permitam uma melhor eficĂĄcia terapĂȘutica, sendo exemplos a terapia combinada, a sĂntese de fĂĄrmacos com mais do que um alvo terapĂȘutico e ainda a utilização de molĂ©culas orgĂąnicas como modeladores enzimĂĄticos. Ao longo desta dissertação serĂĄ apresentada uma revisĂŁo crĂtica do estado da arte no desenvolvimento e otimização de inibidores de topoisomerases.
Neoplasms are amongst the leading causes of death in the 21st century and are characterized by the presence of cells that grow in an uncontrolled and undefined way. The risk of developing neoplasms, whatever its location, increases in the presence of factors such as immunosuppression, that may be related to stress, age and/or the administration of certain drugs, such as corticosteroids, antibacterials, and others. The development of selective and safe anticancer drugs remains as one of the biggest challenges in Pharmaceutical Chemistry. ADN topoisomerases are ubiquitous nuclear enzymes involved in the processes of regulating the topological state of ADN, that increase their activity in the various types of cancer, functioning even as biomarkers. So, topoisomerases are considered as therapeutic targets for anticancer therapy, showing special interest in the development of topoisomerase inhibitors that may be used. The topoisomerase inhibitors, namely type II, are used for the treatment of numerous types of cancer and can be divided, according to their mechanism of action, into, topoisomerase poisons, such as doxorubicin and etoposide, and catalytic inhibitors, like merbarone. However, despite being widely prescribed, these drugs are associated with the possibility of developing serious side effects, such as cardiotoxicity or iatrogenic secondary neoplasm, and also the emergence of resistances. These limitations raise awareness to the need of developing new strategies that allow good therapeutic efficacy, such as combined therapy, the synthesis of drugs with more than one therapeutic target, and the use of organic molecules as enzymatic modelers. Throughout this dissertation, it will be present a critical review of the state of the art in the development and optimization of topoisomerase inhibitors.
Neoplasms are amongst the leading causes of death in the 21st century and are characterized by the presence of cells that grow in an uncontrolled and undefined way. The risk of developing neoplasms, whatever its location, increases in the presence of factors such as immunosuppression, that may be related to stress, age and/or the administration of certain drugs, such as corticosteroids, antibacterials, and others. The development of selective and safe anticancer drugs remains as one of the biggest challenges in Pharmaceutical Chemistry. ADN topoisomerases are ubiquitous nuclear enzymes involved in the processes of regulating the topological state of ADN, that increase their activity in the various types of cancer, functioning even as biomarkers. So, topoisomerases are considered as therapeutic targets for anticancer therapy, showing special interest in the development of topoisomerase inhibitors that may be used. The topoisomerase inhibitors, namely type II, are used for the treatment of numerous types of cancer and can be divided, according to their mechanism of action, into, topoisomerase poisons, such as doxorubicin and etoposide, and catalytic inhibitors, like merbarone. However, despite being widely prescribed, these drugs are associated with the possibility of developing serious side effects, such as cardiotoxicity or iatrogenic secondary neoplasm, and also the emergence of resistances. These limitations raise awareness to the need of developing new strategies that allow good therapeutic efficacy, such as combined therapy, the synthesis of drugs with more than one therapeutic target, and the use of organic molecules as enzymatic modelers. Throughout this dissertation, it will be present a critical review of the state of the art in the development and optimization of topoisomerase inhibitors.
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Keywords
Neoplasia Topoisomerases Inibidores das topoisomerases ADN