RESUMO
A practical, integrated and versatile U-4CR-based assembly of 1,4-benzodiazepin-2-ones exhibiting functionally, skeletally, and stereochemically diverse substitution patterns is described. By virtue of its convergence, atom economy, and bond-forming efficiency, the methodology documented herein exemplifies the reconciliation of structural complexity and experimental simplicity in the context of medicinal chemistry projects.
Assuntos
Benzodiazepinonas/química , Técnicas de Química Combinatória , Estrutura Molecular , Fenômenos de Química Orgânica , EstereoisomerismoRESUMO
The synthesis of new 6,10-dimethylpyridazino[4,5-h]psoralens, carrying no (4), one (5), or two (6-9) dialkylaminoalkylcarboxamide side chains on the pyridazine ring is reported. All compounds exert a significant photoantiproliferative activity. Moreover, the derivatives characterised by the protonable side chains show a notable cytotoxicity in the dark. The investigation on the mechanism of action demonstrated the capacity to intercalate into DNA base pairs and to inhibit the relaxation activity of topoisomerase II.
Assuntos
Furocumarinas/química , Substâncias Intercalantes/química , Piridazinas/química , Linhagem Celular Tumoral , DNA Topoisomerases Tipo II/metabolismo , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/toxicidade , Furocumarinas/síntese química , Furocumarinas/toxicidade , Humanos , Substâncias Intercalantes/síntese química , Substâncias Intercalantes/toxicidade , Inibidores da Topoisomerase II , Raios UltravioletaRESUMO
Following our results with benzopsoralens as potent photochemotherapeutic agents, we report the antiproliferative evaluation of nitrogenated isoster upon and without UVA irradiation. The evaluated pyridazinopsoralen showed a higher photochemotherapeutic activity with respect to the well-known drug, 8-MOP, and a significant cytotoxicity, also in the dark. This result enlarges the interest in this tetracyclic psoralen derivative skeleton in the search of new anticancer agents.
Assuntos
Antineoplásicos/química , Ficusina/química , Fármacos Fotossensibilizantes/química , Piridazinas/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/toxicidade , Linhagem Celular , Ficusina/síntese química , Ficusina/toxicidade , Cobaias , Células HeLa , Humanos , Metoxaleno/toxicidade , Fármacos Fotossensibilizantes/síntese química , Piridazinas/síntese química , Piridazinas/toxicidade , Raios UltravioletaRESUMO
The inverse electron-demand Diels-Alder reaction between furocoumarinones and 3,6-bis(methoxycarbonyl)-1,2,4,5-tetrazine was used to give pyridazinofurocoumarins in good yields. The structural characterisation of the synthesised compounds was achieved by NMR spectroscopy. The mass spectrometric behaviour was studied under electron ionisation conditions via sequential product ion fragmentation experiments (MS(n)). This study allowed the evaluation of the role played by the methyl substituent on the benzene ring of pyridazinofurocoumarins in their fragmentation pathways.
