Approaches to phenazine‐derived N ‐isosteres of anthracyclinones

1‐Hydroxyphenazine 5,10‐dioxide showed antitumor properties against mouse leukemia P388. It also participated in biochemical mechanisms of quinoid antitumor agents, as indicated by inhibition of radiolabeled DNA‐RNA precursors in cultured leukemia L1210 cells and by stimulation of oxygen consumption in mammalian microsomes. This suggests that the isosteric di‐ N ‐oxide system may be a biologically active substitute for 1,4‐quinone, and that di‐ N ‐oxides of tetrahydrobenzo[ b ]phenazines can be explored as anthracyclinone N ‐isosteres. As potential synthetic intermediates, 7,8,9,10‐tetrahydro‐6,11‐dihydroxybenzo[ b ]‐phenazines have been prepared by 1) Diels‐Alder addition of phenazine‐1,4‐quinone and 1‐methoxy‐3‐(trimethylsilyloxy)‐1,3‐butadiene to give isolable but labile adducts and 2) condensation of 6,7‐diamino‐1,2,3,4‐tetrahydro‐2‐hydroxy‐5,8‐dimethoxy‐2‐naphthoic acid with 3‐methoxy‐1,2‐quinone. Attempts at N ‐oxidation gave instead oxidation of the 6,11‐hydroquinone ring to quinone, regardless of hydroxyl protection. Despite previous literature indications, we have been unable to synthesize the 1,4‐dihydroxyphenazine 5,10‐dioxide system. We conclude that this hydroxyl substitution pattern (1,4) in an adjacent ring must be avoided in the redesign of anthracyclinone isosteres that have di N ‐oxide in place of quinone.