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Antitumor Agents. 5. Synthesis, Structure−Activity Relationships, and Biological Evaluation of Dimethyl-5H-pyridophenoxazin-5-ones, Tetrahydro-5H-benzopyridophenoxazin-5-ones, and 5H-Benzopyridophenoxazin-5-ones with Potent Antiproliferative Activity

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journal contribution
posted on 24.08.2006, 00:00 by Adele Bolognese, Gaetano Correale, Michele Manfra, Antonio Lavecchia, Ettore Novellino, Stefano Pepe
New antiproliferative compounds, dimethyl-5H-pyrido[3,2-a]phenoxazin-5-ones (16), tetrahydro-5H-benzopyrido[2,3-j]phenoxazin-5-ones (79), and 5H-benzopyrido[3,2-a]phenoxazin-5-ones (1012) were synthesized and evaluated against representative human neoplastic cell lines. Dimethyl derivatives 16 were more active against carcinoma than leukemia cell lines. The tetrahydrobenzo derivatives 79 were scarcely active, whereas the corresponding benzo derivatives 1012 showed notable cytotoxicity against a majority of the tested cell lines. Molecular modeling studies indicated that the high potency of 10 and 11, the most cytotoxic compounds of the whole series, could be due to the position of the condensed benzene ring, which favors π−π stacking interactions with purine and pyrimidine bases in the DNA active site. Biological studies suggested that 1012 have no effect on human topoisomerases I and II and that they induce arrest at the G2/M phase.