RESUMO
The synthesis of N-{4-[a-(1-adamantyl)benzyl]phenyl}piperazines 2a-e is described. The in vitro antiproliferative activity of most compounds against main cancer cell lines is significant. The σ(1), σ(2)-receptors and sodium channels binding affinity of compounds 2 were investigated. One of the most active analogs, 2a, had an interesting in vivo anticancer profile against the BxPC-3 and Mia-Paca-2 pancreas cancer cell lines with caspase-3 activation, which was associated with an anagelsic activity against the neuropathic pain.
Assuntos
Adamantano , Antineoplásicos , Receptores sigma/metabolismo , Adamantano/síntese química , Adamantano/química , Adamantano/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Camundongos , Camundongos Nus , Estrutura Molecular , Neoplasias Pancreáticas/metabolismoRESUMO
The synthesis of the adamantane phenylalkylamines 2a-d, 3a-c, and 4a-e is described. These compounds exhibited significant antiproliferative activity, in vitro, against eight cancer cell lines tested. The σ(1), σ(2), and sodium channel binding affinities of compounds 2a, 3a, 4a, and 4c-e were investigated. The most interesting analogue, 4a, exhibited significant in vivo anticancer profile on pancreas, prostate, leukemia, and ovarian cancer cell line xenografts together with apoptosis and caspase-3 activation. Inhibition of the cancer cells cycle at the sub-G1 level was also obtained with 4a. Finally, encouraging results were observed with 4a in vivo on mice, suggesting putative antimetastatic and analgesic activities of this compound.
Assuntos
Adamantano/análogos & derivados , Adamantano/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neuralgia/tratamento farmacológico , Piperidinas/farmacologia , Receptores sigma/metabolismo , Adamantano/síntese química , Adamantano/farmacologia , Animais , Antineoplásicos/síntese química , Caspase 3/metabolismo , Ciclo Celular/efeitos dos fármacos , Feminino , Humanos , Masculino , Camundongos , Camundongos SCID , Estrutura Molecular , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Piperidinas/síntese química , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Ligação Proteica , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
The synthesis of 4-(1-adamantyl)-4,4-diarylbutylamines 1, 5-(1-adamantyl)-5,5-diarylpentylamines 2 and 6-(1-adamantyl)-6,6-diarylhexylamines 3 is described and the σ1, σ2-receptors and sodium channels binding affinity of compounds 1 were investigated. The in vitro activity of compounds 1, 2 and 3 against main cancer cell lines is significant. One of the most active analogs, 1a, had an interesting in vivo anticancer profile against the ovarian cancer cell line IGROV-1, which was associated with an anagelsic activity against the neuropathic pain induced by the main anticancer drugs.
Assuntos
Adamantano/química , Adamantano/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Receptores sigma/química , Adamantano/síntese química , Adamantano/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/uso terapêutico , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Feminino , Humanos , Masculino , Camundongos , Camundongos SCID , Neoplasias/tratamento farmacológicoRESUMO
The Wilms' tumour 1 (WT1) protein is over-expressed in several types of cancer including leukaemias and might therefore constitute a novel target for immunotherapy. Recently, human leucocyte antigen (HLA) class I-binding WT1 peptides have been identified and shown to stimulate CD8(+) T cells in vitro. For maximal CD8 cell efficacy, CD4(+) helper T cells responding to major histocompatibility complex (MHC) class II-binding epitopes are required. Here, we report that scanning the WT1 protein sequence using an evidence-based predictive computer algorithm (SYFPEITHI) yielded a peptide WT1(124-138) predicted to bind the HLA-DRB1*0401 molecule with high affinity. Moreover, synthetic WT1(124-138)-peptide-pulsed dendritic cells (DC), generated according to a protocol optimised in the present study, sensitised T cells in vitro to proliferate and secrete interferon-gamma (IFN-gamma) when rechallenged with specific peptide-pulsed DC, but not with peripheral blood mononuclear cells (PBMC). These results suggest that the WT1 protein may yield epitopes immunogenic to CD4 as well as CD8 T cells, and therefore constitute a novel potential target for specific immunotherapy.