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

Abstract

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 pi-pi 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.

Use of 2-aminoprop-1-ene-1,1,3-tricarbonitrile for the synthesis of tetrahydronaphthalene, hexahydroisoquinoline and hexahydrocinnoline derivatives with potential antitumor activities

“…IR spectra (u, cm -1 ) were recorded in KBr pellets on a PA-9721 IR spectrophotometer (Shimadzu, Japan). 1 H NMR and 13 C NMR spectra were obtained on a Jeol 300 MHz (Japan) spectrometer in DMSO-d 6 as solvent, using TMS as internal reference, and chemical shifts (d) are expressed in ppm. Mass spectra were recorded on Kratos (75 eV) MS equipment (Germany).…”

Microwave-Assisted Synthesis of Pyridophenoxazinones, a Class of Antiproliferative Compounds

“…The conventional synthetic method to prepare PPXZ derivatives as 1–11 , which involves the reaction of an equimolar amount of quinoline‐5,8‐dione (QQ) and of substituted 2‐aminophenols (APhOHs) in refluxing glacial acetic acid for 24 h, is not very effective owing to rather harsh reaction conditions and produces the poorest yields. Several side products, like phenoxazines ( 14 ), aminophenoxazin‐3‐ones ( 15 ), triphenodioxazines ( 16 ), are reported to accompany the desired PPXZs (Figure ). A large amount of black, intractable polymeric materials are also formed, thus decreasing significantly the yields of PPXZs and also encumbering the subsequent purification procedures of the final reaction mixtures.…”

Synthesis and characterization of n-alkylamino derivatives of vitamin K3: Molecular structure of 2-propylamino-3-methyl-1,4-naphthoquinone and antibacterial activities

“…The flavoprotein-catalyzed redox cycling of quinones in cells would, therefore, quickly lead to conditions of oxidative stress due to excess of the superoxide radical. These oxygen intermediates or reactive oxygen species (ROS) may react directly with DNA or other biomolecules such as proteins and lipids, which leads to cell damage [21][22][23][24]. In in vivo, the flavoprotein NAD(P)H which is a quinone-acceptor oxidoreductase, catalyzes the two-electron reduction of quinones to hydroquinones without the formation of semiquinone radical intermediates, whereas NADPH-cytochrome P-450 reductase and NADH-ubiquinone oxidoreductase catalyze the one-electron reduction of quinones to semiquinone radicals.…”