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Complexos de elementos emissores de radiação gama e de electrões Auger para diagnóstico e/ou terapia do cancro
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Novos ligandos do tipo pirazolo-diamina com as unidades intercaladoras alaranjado de
acridina (L1, L3), 9-acridina ácido carboxílico (L2, L4) e antraceno (L5), na posição 4 do anel
de pirazolilo, foram sintetizados e caracterizados. A sua coordenação à unidade fac-[M(CO)3]+
(M=Re,99mTc) originou complexos do tipo fac-[M(CO)3(κ3-L)]+/2+ em que: L=L1: M= Re (Re1),
99mTc (Tc1); L=L2: M= Re (Re2), 99mTc (Tc2); L=L3: M= Re (Re3), 99mTc (Tc3); L=L4:
M=Re (Re4); L=L5: M= Re (Re5), 99mTc (Tc5). A interacção de L1 e L2 e dos respectivos
complexos Re1 e Re2 com ADN de timo de vitela foi avaliada por várias técnicas
espectroscópicas. Os compostos L1 e Re1 demonstraram afinidade para o ADN interactuando
com ele por intercalação, enquanto L2 e Re2 possuiam uma fraca afinidade. Os resultados de
LD mostraram que L1 e Re1 se comportavam como intercaladores perfeitos. Por microscopia
confocal de fluorescência verificou-se que L1, L3, Re1 e Re3 internalizavam em células B16-F1
e/ou PC-3, localizando-se no núcleo, comportamento confirmado e quantificado com estudos
que envolveram as mesmas linhas celulares e o complexo Tc1. Estudos com ADN plasmídico
puc19 demonstraram que Tc1 convertia a forma superenrolada do ADN na forma circular, por
indução de quebras simples. Para explorar a potencial aplicação terapêutica do 99mTc como
emissor Auger, análogos da bombesina (BBN) do tipo X-BBN[7-14] (X=SGS, GGG, NLS) foram
ligados a L3 originando os conjugados peptídicos L6 (SGS), L7 (GGG) e L11 (NLS). Complexos
do tipo fac-[99mTc(CO)3(κ3-L)]2+ (L=L6 (Tc6); L=L7 (Tc7); L=L11 (Tc11)) foram
seguidamente isolados e caracterizados por comparação do seu perfil cromatográfico com o dos
correspondentes complexos de rénio (Re6, Re7, Re11). Estudos com células tumorais
confirmaram que Re6/Tc6 e Re7/Tc7 eram selectivos para as células PC-3 e que se
acumulavam no núcleo. A translocação do complexo Tc11 do citoplasma para o núcleo
aumentou devido à presença da sequência peptídica NLS.
Novel pyrazolyl-diamine ligands with the intercalating units acridine orange (L1, L3), 9- acridine carboxylic acid (L2, L4) and anthracene (L5), at the 4-position of the pyrazolyl ring, were synthesized and characterized. Coordination towards the fac-[M(CO)3]+ core (M = Re, 99mTc) led to complexes of the type fac-[M(CO)3(κ3-L)]+/2+ where: L =L1: M =Re (Re1), 99mTc (Tc1); L =L2: M =Re (Re2), 99mTc (Tc2); L =L3: M =Re (Re3), 99mTc (Tc3); L =L4: M= Re (Re4); L =L5: M= Re (Re5), 99mTc (Tc5). The interaction of L1 and L2 and complexes Re1 and Re2 with calf thymus DNA was investigated by a variety of spectroscopic techniques. Compounds L1 and Re1 had moderate affinity to DNA interacting with it by intercalation, while L2 and Re2 had poor affinity. LD measurements showed that L1 and Re1 acted as perfect intercalators. By confocal fluorescence microscopy we found that L1, L3, Re1 and Re3 internalized in B16-F1 and/or PC-3 cells, localizing in their nucleus, which was confirmed and quantified in studies involving the same cell lines and complex Tc1. DNA studies with puc19 plasmid showed that Tc1 converted supercoiled DNA to the open circular form, by induction of single strand breaks. To explore the potential therapeutic usefulness of 99mTc as an Auger emitter, bombesin analogues of the type X-BBN[7-14] (X=SGS, GGG, NLS) were conjugated to L3 leading to conjugates L6 (SGS), L7 (GGG) and L11 (NLS). Complexes of the type fac- [99mTc(CO)3(κ3-L)]2+ (L=L6 (Tc6); L=L7 (Tc7); L=L11 (Tc11)) were isolated and characterized by comparison of their chromatographic profiles with the ones of the corresponding rhenium complexes (Re6, Re7, Re11). Studies with tumor cells confirmed that Re6/Tc6 and Re7/Tc7 had selectivity for PC-3 cells and that they accumulated in their nucleus. The translocation of complex Tc11 from cytoplasm to the nucleus was enhanced due to the presence of the NLS sequence.
Novel pyrazolyl-diamine ligands with the intercalating units acridine orange (L1, L3), 9- acridine carboxylic acid (L2, L4) and anthracene (L5), at the 4-position of the pyrazolyl ring, were synthesized and characterized. Coordination towards the fac-[M(CO)3]+ core (M = Re, 99mTc) led to complexes of the type fac-[M(CO)3(κ3-L)]+/2+ where: L =L1: M =Re (Re1), 99mTc (Tc1); L =L2: M =Re (Re2), 99mTc (Tc2); L =L3: M =Re (Re3), 99mTc (Tc3); L =L4: M= Re (Re4); L =L5: M= Re (Re5), 99mTc (Tc5). The interaction of L1 and L2 and complexes Re1 and Re2 with calf thymus DNA was investigated by a variety of spectroscopic techniques. Compounds L1 and Re1 had moderate affinity to DNA interacting with it by intercalation, while L2 and Re2 had poor affinity. LD measurements showed that L1 and Re1 acted as perfect intercalators. By confocal fluorescence microscopy we found that L1, L3, Re1 and Re3 internalized in B16-F1 and/or PC-3 cells, localizing in their nucleus, which was confirmed and quantified in studies involving the same cell lines and complex Tc1. DNA studies with puc19 plasmid showed that Tc1 converted supercoiled DNA to the open circular form, by induction of single strand breaks. To explore the potential therapeutic usefulness of 99mTc as an Auger emitter, bombesin analogues of the type X-BBN[7-14] (X=SGS, GGG, NLS) were conjugated to L3 leading to conjugates L6 (SGS), L7 (GGG) and L11 (NLS). Complexes of the type fac- [99mTc(CO)3(κ3-L)]2+ (L=L6 (Tc6); L=L7 (Tc7); L=L11 (Tc11)) were isolated and characterized by comparison of their chromatographic profiles with the ones of the corresponding rhenium complexes (Re6, Re7, Re11). Studies with tumor cells confirmed that Re6/Tc6 and Re7/Tc7 had selectivity for PC-3 cells and that they accumulated in their nucleus. The translocation of complex Tc11 from cytoplasm to the nucleus was enhanced due to the presence of the NLS sequence.
Descrição
Tese de doutoramento, Química (Química Inorgânica), Universidade de Lisboa, Faculdade de Ciências, 2011
Palavras-chave
Radiofármacos Complexos organometálicos ADN Electrões Teses de doutoramento - 2011