title: Total chemical synthesis and antitumor evaluation of the 9-aza analogue of N-(trifluoroacetyl)-4-demethoxydaunomycin.
abstract: The 9-aza analogue of N-(trifluoroacetyl)-4-demethoxydaunomycin has been synthesized from 2,5-dimethoxybenzaldehyde. Pomeranz-Fritsch condensation followed by borohydride reduction and acid-catalyzed cyclization led smoothly to 4-hydroxy-5,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline. Selective N-acetylation and subsequent Friedel-Crafts acylation with phthalic anhydride produced 2-acetyl-5,12-dihydroxy-1,2-dihydro-2-azanaphthacene-6,11-dione, which was protected as its dimethyl ether and epoxidized to an acylated aza Brigl's anhydride. This was converted to (+/-)-2-acetyl-4-hydroxy-5,12-dimethoxy-1,2,3,4-tetrahydro-2- azanaphthacene-6,11-dione by dehydration to the 4-keto analogue followed by cyanoborohydride reduction either stepwise or in situ. The protecting groups were removed with boron trichloride and the resulting aglycone glycosidated with optically active N,O-bis(trifluoroacetyl)daunosamine bromide and silver trifluoromethanesulfonate. The resulting diastereoisomers were separated by column chromatography and their structures established by CD and NMR spectroscopy. Unexpectedly it was not possible to remove the N-trifluoroacetyl blocking group without aromatization to the azanaphthaquinone. Both (R)- and (S)-acetyl-4-O-[N-(trifluoroacetyl)daunosaminyl]-5,12-dihydroxy-2- azanaphthacene-6,11-dione were inactive ip in mice carrying the P388 tumor. Drugs were given at various concentrations on days 0, 5, and 9.
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D001372:Aza Compounds; D002942:Circular Dichroism; D003630:Daunorubicin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D007202:Indicators and Reagents; D007941:Leukemia P388 / Q000188:drug therapy; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001372:Aza Compounds; D007202:Indicators and Reagents; D003630:Daunorubicin