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

Cell growth-inhibition and cell cycle perturbations induced by a new synthetic iminoquinone, 5H-pyridophenoxazin-5-one, in human breast carcinoma cell lines.

5H-Pyridophenoxazin-5-one (PPH) is a new synthetic iminoquinone which has showed to be a potent cytotoxic agent on different cancer cell lines. PPH effects depend by the intercalation into the DNA double strand at the middle 5′-GC-3′ base pairs of the octamer [d(GAAGCTTC)2] and the production, under bio reductive conditions, of free oxygen radicals. The aim of the study was to analyse cell growth and cell cycle kinetics of MCF-7 (p53 wt) and MDA-MB-468 (p53 mut) human breast cancer cell lines after PPH exposure. Treatments were performed with different PPH concentrations (ranging from 0.5 μM up 8 μM) as pulsed (60 min/exposure) or continuous exposure. MCF-7 cells were more sensitive to pulsed treatment than MDA-MB-468 cell line. Cell cycle analysis by PI staining showed a G2M perturbation that was overcome after 72 hours in both cell lines. As expected, continuous treatment caused a strongest cell-growth inhibition and cell cycle perturbation in both cell lines. However, DNA-flow cytometry showed that MCF-7 cells cytotoxicity correlate with an accumulation of cells in the S phase, whereas an irreversible G2M block accompanied MDA-MB-468 cytotoxicity