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

New antiproliferative compounds, dimethyl-5H-pyrido[3,2-a]phenoxazin-5-ones (1−6), tetrahydro-5H-benzopyrido[2,3-j]phenoxazin-5-ones (7−9), and 5H-benzopyrido[3,2-a]phenoxazin-5-ones (10−12) were synthesized and evaluated against representative human neoplastic cell lines. Dimethyl derivatives 1−6 were more active against carcinoma than leukemia cell lines. The tetrahydrobenzo derivatives 7−9 were scarcely active, whereas the corresponding benzo derivatives 10−12 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 10−12 have no effect on human topoisomerases I and II and that they induce arrest at the G2/M phase.