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Complexos de metais do grupo VIII na terapêutica antitumoral: passado, presente e futuro
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O cancro, caracterizado por um crescimento celular desregulado, é atualmente uma das
principais causas de morte no mundo. Devido à diversidade, quer de mecanismos de
crescimento, quer de locais alvo, o tratamento do cancro continua a ser um desafio para a
comunidade científica.
Desde a descoberta acidental da cisplatina como agente antitumoral, diversos grupos de
investigação têm-se debruçado sobre o desenvolvimento de novos compostos de coordenação
com potencial antineoplásico.
Os compostos de ferro, um metal essencial em sistemas biológicos, apresentam um
mecanismo de ação associado a reações redox envolvendo o par Fe(II)/Fe(III). A perturbação
de diversos equilíbrios redox ou a promoção de uma reação redox que por um mecanismo
radicalar possa dar origem a danos irreparáveis em diferentes biomoléculas faz deste metal um
candidato no desenvolvimento de complexos com ação citotóxica como é já o caso do complexo
Fe-bleomicina.
Os compostos de ruténio têm demonstrado beneficiar de características que os tornam
promissores agentes antitumorais, pela riqueza das suas propriedades químicas, conquistando,
atualmente, um papel importante na investigação de terapêuticas contra o cancro. Estes
compostos destacam-se pela reduzida toxicidade, boa tolerância in vivo e pelos diferentes
mecanismos de ação, contando já com dois complexos usados em ensaios clínicos em humanos,
NAMI-A e KP1019/NKP1339.
Por fim, estudos recentes mostram que o ósmio apresenta reatividade química e os seus
complexos podem ser ajustados pela escolha do seu estado de oxidação, dos ligandos e da
geometria de coordenação e estereoquímica, abrindo assim uma ampla gama de novas
aplicações biológicas e médicas. A terapêutica antitumoral com recurso a estes complexos pode
ter diversos mecanismos de ação e alvos, incluindo interações com o ADN, atividade redox e
inibição de proteínas.
A presente dissertação centra-se nas potencialidades dos complexos de metais do grupo
VIII na terapêutica antitumoral. É efetuada uma revisão bibliográfica aprofundada e crítica dos
resultados obtidos em diversos estudos que envolveram ou envolvem complexos dos três metais
deste grupo.
Cancer, a set of pathologies that share deregulated cell growth, is currently one of the leading causes of death in the world. Due to the diversity of both growth mechanisms and target sites, cancer treatment remains a challenge for the scientific community. Since the accidental discovery of cisplatin as an antitumor agent, several research groups have focused on the development of new coordination compounds with antineoplastic potential. Iron compounds, an essential metal in biological systems, have a mechanism of action associated with redox reactions involving the Fe(II)/Fe(III) pair. The disturbance of several redox balances or the promotion of a redox reaction that, by a radical mechanism, can give rise to irreparable damage in different biomolecules, makes this metal a candidate in the development of complexes with cytotoxic action, as it is already the case of the Fe-bleomycin complex. Ruthenium compounds have shown to benefit from characteristics that make them promising antitumor agents, due to the richness of their chemical properties, currently conquering an important role in the research of cancer therapies. These compounds stand out for their reduced toxicity, good tolerance in vivo and for the different mechanisms of action by which they act, already counting on two complexes used in clinical trials in humans, NAMI-A and KP1019/ NKP1339. Finally, recent studies show that osmium presents chemical reactivity and its complexes can be adjusted by the choice of its oxidation state, ligands, and coordination and stereo chemical geometry, thus opening up a wide range of new biological and medical applications. Antitumor therapy using these complexes may have several mechanisms of action and targets, including DNA interactions, redox activity, and protein inhibition. This dissertation focuses on the potentialities of group VIII metal complexes in antitumor therapy. A thorough and critical literature review of the results obtained in several studies involving complexes of the three metals in this group is carried out.
Cancer, a set of pathologies that share deregulated cell growth, is currently one of the leading causes of death in the world. Due to the diversity of both growth mechanisms and target sites, cancer treatment remains a challenge for the scientific community. Since the accidental discovery of cisplatin as an antitumor agent, several research groups have focused on the development of new coordination compounds with antineoplastic potential. Iron compounds, an essential metal in biological systems, have a mechanism of action associated with redox reactions involving the Fe(II)/Fe(III) pair. The disturbance of several redox balances or the promotion of a redox reaction that, by a radical mechanism, can give rise to irreparable damage in different biomolecules, makes this metal a candidate in the development of complexes with cytotoxic action, as it is already the case of the Fe-bleomycin complex. Ruthenium compounds have shown to benefit from characteristics that make them promising antitumor agents, due to the richness of their chemical properties, currently conquering an important role in the research of cancer therapies. These compounds stand out for their reduced toxicity, good tolerance in vivo and for the different mechanisms of action by which they act, already counting on two complexes used in clinical trials in humans, NAMI-A and KP1019/ NKP1339. Finally, recent studies show that osmium presents chemical reactivity and its complexes can be adjusted by the choice of its oxidation state, ligands, and coordination and stereo chemical geometry, thus opening up a wide range of new biological and medical applications. Antitumor therapy using these complexes may have several mechanisms of action and targets, including DNA interactions, redox activity, and protein inhibition. This dissertation focuses on the potentialities of group VIII metal complexes in antitumor therapy. A thorough and critical literature review of the results obtained in several studies involving complexes of the three metals in this group is carried out.
Descrição
Palavras-chave
Cancro Terapêutica anticancerígena Metal Compostos de ruténio Compostos de ósmio Compostos de ferro