TAUTOMERIC INSTABILITY OF 10-DEOXYDAUNOMYCINONE HYDROQUINONE

10-Deoxydaunomycinone and daunomycin are reduced by excess sodium dithionite, under anaerobic conditions, to 10-deoxydaunomycinone hydroquinone. This hydroquinone is not stable, having an approximate rate constant (in 48% MeHO, 52% H2O, 10 mM Tris-HCl, 10 mM Tris base) for its disappearance of 2 .times. 10-4 s-1. This disappearance results from a number of tautomeric equilibria, which transform this hydroquinone into more stable species. Typically, eight products in addition to 10-deoxydaunomycinone are detected by reverse-phase liquid chromatographic analysis of the product mixture. Thus far seven of these products have been identified and characterized. Three of the products are diastereomers of (2R)-2-acetyl-1,2,3,4,4a,12a-hexahydro-2,6,11-trihydroxy-7-methoxy-5,12-naphthacenedione that have differing stereochemistry at the C-4a,C-12a ring juncture. The major diastereomer (50% of the product) has a trans ring juncture, while the other two diastereomers, (13% and 5% of the product) both have a cis ring juncture. Two of the products formed, (2R)-2-acetyl-1,2,3,4-tetrahydro-2,11-dihydroxy-7-methoxy-5,12-naphthacenedione (4% of the product) and (2R)-2-acetyl-1,2,3,4-tetrahydro-2,6-dihydroxy-7-methoxy-5,12-naphthacenedione (2% of the product), involve the loss of an oxygen from the anthracycline''s C ring. The last two products, (8R)-8-acetyl-7,9,10,12-tetrahydro-6,8,11-trihydroxy-1-methoxy-5(8H)-naphthacenone (11% of the product) and (9R)-9-acetyl-7,9,10,12-tetrahydro-6,9,11-trihydroxy-4-methoxy-5(8H)-naphthacenone (5% of the product), are derived from the reduction of the dihydroxynaphthacenediones by the excess dithionite present in the mixture. The effect of Fe(III) ion chelation of the anthracycline on the anaerobic dithionite reduction of both daunomycin and 10-deoxydaunomycinone is examined. A modest rate increase for the tautomerization of the hydroquinone is observed for the anaerobic dithionite reduction of the 10-deoxydaunomycinone-Fe(III) chelate, whereas little effect is observed for the daunomycin-Fe(III) chelate. This surprising diversity of materials may account for the abundance of aglycon metabolites found in vivo (many as yet uncharacterized), may prove of value in the synthetic elaboration of anthracyclinones, and is likely to be representative of the hydroquinone behavior of the p-dihydroxyanthracyclinones of the rhodomycinone, isorhodomycinone, and pyrromycinone families.