Caracterização da atividade antitumoral das tiossemicarbazonas derivadas de N(4)-Metil-Toluil-2-acetilpiridina e de 2-piridinoformamida e seus complexos metálicos: avaliação do potencial radiofarmaceutico / CHARACTERIZATION OF THE ANTITUMURAL ACTIVITY OF THE THIOSEMICARBAZONES DERIVED FROM N(4)-METHYL-TOLYL-2- ACETYLPYRIDINE AND 2-PIRIDINOFORMAMIDE AND ITS METAL COMPLEX: EVALUATION OF THE RADIOPHARMACEUTICAL POTENTIAL.

AUTOR(ES)
DATA DE PUBLICAÇÃO

2008

RESUMO

Thiosemicarbazones have attracted great pharmacological interest because of their biological properties, such as cytotoxic activity against multiple strains of human tumors. The most studied compounds are pyridine-based because of their resemblance to pyridoxal metabolites that attach to co-enzyme B6-dependant enzymes. This work aimed the characterization of the antitumoral effect of N(4)-methyl-tolyl-2-acetilpiridine and 2- pyridinoformamidederived thiosemicarbazones and the development of a radiopharmaceutical based on a thiosemicarbazone metal complex for positron emission tomography. In the first phase of this study were synthesized twenty-one thiosemicarbazones, derived from N(4)methyl-2 acetylpyridine and 2-pyridineformamide, as well as their metal complexes (Sn, Ga and Cu). Their cytotoxic potential were evaluated against brain and breast tumor cells in vitro. Our results showed all of them presented powerful cytotoxic and antiproliferative activities against glioblastoma multiforme and breast adenocarcinoma at very low concentrations (nanomolar range). Morphological alterations characteristic of apoptosis, such as cell shrinkage, chromatin condensation were observed. Copper chloride was used as control and has presented IC50 at milimolar range suggesting that copper complexation with thiosemicarbazone significantly increases (more than 1 million) the antitumoral effect of this metal. Due to the potent antitumoral activity of N(4)-methyl-tolyl-2-acetilpiridine derived thiosemicarbazones and the excellent properties of 64Cu (T1/2 = 12.7 hours, β+, β-, and EC decay), at the second part for this work it was developed a new imaging agent (radiopharmaceutical) for tumor detection by positron emission tomography (PET). The radiopharmaceuticals were produced in the nuclear reactor TRIGA-IPR-R1 from CDTN, via neutron capture reaction 63Cu (n,γ) 64Cu, of the copper complex N(4)-ortho-toluyl-2- acetylpyridine thiosemicarbazone (Culac). The induced specific activity was found to be 5.55 MBq /mg. After irradiation 64Culac samples were analyzed by the absorption of infrared spectroscopy (IR) to assess the structural integrity. The irradiated compound kept its structural integrity. The maintenance of 64Culac biological activity was also evaluated by MTT assay on RT2 (wild p53), T98 (mutant p53), MCF-7 (wild p53) and CAE cells (wild p53). The results showed that 64Culac kept its potent antitumural activity against all treated cells presenting IC50 values at nanomolar range. 64Culac biodistribution studies after intravenous injection in mice bearing Erlich tumor implanted in the paw, showed significant uptake in the tumor paw (tumor/skeletal muscle ratio= 6.55), 240 minutes after administration. Histopathological studies have shown mild hepatotoxicity 144 hours (6 days) after intravenous administration of 308 mg/kg of Culac. However, no lethality, behavioural, or feeding changes were observed at this dose. Our results demonstrate that the complex of copper-64 N(4)-ortho-toluyl-2- acetylpyridine thiosemicarbazone (64Culac) is a promising radiopharmaceutical for detection of solid tumors by positron emission tomography (PET).

ASSUNTO(S)

medicina nuclear neoplasms cancerologia radiofármacos nuclear medicine tomografia por emissão de positron radiopharmaceuticals neoplasias

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