RESUMO
The synthesis of a diverse library of compounds structurally related to maprotiline, a norepinephrine reuptake transporter (NET) selective antidepressant which has recently been identified as a novel in vitro antiproliferative agent against Burkitt's lymphoma (BL) cell lines is reported. A series of 9,10-dihydro-9,10-ethanoanthracenes were synthesised with modifications to the bridge of the dihydroethanoanthracene structure and with alterations to the basic side chain. A number of compounds were found to reduce cell viability to a greater extent than maprotiline in BL cell lines. In addition a related series of novel 9-substituted anthracene compounds were investigated as intermediates in the synthesis of 9,10-dihydro-9,10-ethanoanthracenes. These compounds proved the most active from the screen and were found to exert a potent caspase-dependant apoptotic effect in the BL cell lines, while having minimal effect on the viability of peripheral blood mononuclear cells (PBMCs). Compounds also displayed activity in multi-drug resistant (MDR) cells.
Assuntos
Inibidores da Captação Adrenérgica/farmacologia , Antineoplásicos/farmacologia , Linfoma de Burkitt/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Maprotilina/farmacologia , Inibidores da Captação Adrenérgica/síntese química , Inibidores da Captação Adrenérgica/química , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Maprotilina/análogos & derivados , Maprotilina/síntese química , Proteínas da Membrana Plasmática de Transporte de SerotoninaRESUMO
Three potent antidepressants, (R)-nisoxetine, lortalamine, and oxaprotiline, with high affinity and high selectivity for the norepinephrine transporter (NET) were synthesized and radiolabeled with C-11 via [11C]methylation. The reference compounds and their corresponding normethyl precursors were synthesized via multi-step synthetic approaches. The radiochemical syntheses were performed by simple alkylation of the corresponding normethyl precursors with no-carrier-added [11C]CH3I in DMF. After HPLC purification, (R)-[N-11CH3]nisoxetine, [11C]lortalamine, and [11C]oxaprotiline were obtained in 63-97% radiochemical yields, whereas (R)-[O-11CH3]nisoxetine was obtained in 23-29% radiochemical yields due to substantial formation of the undesired N-[11C]methylated byproduct (64-70%). These C-11 labeled tracers allowed us to carry out comparative studies of NET in baboons with positron emission tomography (PET) and evaluate their potential as PET tracers for imaging brain NET.