ABSTRACT
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.
Subject(s)
Benzodiazepinones/chemistry , Combinatorial Chemistry Techniques , Molecular Structure , Organic Chemistry Phenomena , StereoisomerismABSTRACT
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.
Subject(s)
Furocoumarins/chemistry , Intercalating Agents/chemistry , Pyridazines/chemistry , Cell Line, Tumor , DNA Topoisomerases, Type II/metabolism , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/toxicity , Furocoumarins/chemical synthesis , Furocoumarins/toxicity , Humans , Intercalating Agents/chemical synthesis , Intercalating Agents/toxicity , Topoisomerase II Inhibitors , Ultraviolet RaysABSTRACT
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.
Subject(s)
Antineoplastic Agents/chemistry , Ficusin/chemistry , Photosensitizing Agents/chemistry , Pyridazines/chemistry , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/toxicity , Cell Line , Ficusin/chemical synthesis , Ficusin/toxicity , Guinea Pigs , HeLa Cells , Humans , Methoxsalen/toxicity , Photosensitizing Agents/chemical synthesis , Pyridazines/chemical synthesis , Pyridazines/toxicity , Ultraviolet RaysABSTRACT
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.
