A Kinetic Rationale for the Inefficiency of 5-Iminodaunomycin as a Redox Catalyst

Article abstract of DOI:10.1021/ja00247a034

The redox chemistry of 5-iminodaunomycin (1) is compared with the redox chemistry of daunomycin (2) to establish a possible rationale for the inefficiency of 5-iminodaunomycin as an in vivo redox catalyst for the production of reactive oxygen species.Anaerobic reduction of 1 with sodium dithionite in methanol solvent gives 5-imino-7-deoxydaunomycinone (3) most likely via the intermediate quinone methide 6.The slow step is tautomerization of 6 to 3, a pseudo-first-order process with a rate-constant of 2.2x10^-2 s^-1 at 25 deg C.Anaerobic reduction of 3 with sodium dithionite in methanol solvent gives 2-acetyl-2,11-dihydroxy-7-methoxy-1,2,3,4-tetrahydro-5,12-naphthacenedione (4) most likely via the intermediate naphthacenone 8.The slow step, proposed to be loss of ammonia, occurs with a rate constant of 4.0x10^-2 s^-1 at 25 deg C.Even traces of molecular oxygen interfere with these two reductions, hence 1 and 3 should be efficient catalysts for the production of reactive oxygen species.Reduction of 4 with sodium dithionite in anaerobic methanol or methanol purged with 2percent oxygen rapidly gives 8-acetyl-1-methoxy-7,9,10,12-tetrahydro-6,8,11-trihydroxy-5(8H)-naphthacenone (9).Naphthacenone 9 is slowly oxidized back to 4 by molecular oxygen with a pseudo-first-order rate constant of 3.3x10^-4 s^-1.Although reduction of daunomycin by sodium dithionite in parallel fashion gives 7-deoxydaunomycinone (5), reduction of 7-deoxydaumycinone does not rapidly give 4 but slowly gives 2-acetyl-1,2,3,4,4a,12a-hexahydro-2,6,11-trihydroxy-7-methoxy-5,12-naphthacenedione (11) with a rate constant of 1.5x10^-4 s^-1.Naphthacenedione 11 is reasonably insensitive to molecular oxygen.Upon standing in the presence of oxygen very slow elimination to give 4 and oxidation to give 5 occur.Consequently, a possible explanation for the inefficiency of 5-iminodaunomycin for catalyzing in vivo the reduction of molecular oxygen is the facile formation of naphthacenedione 4 which is an inefficient catalyst.The inefficiency arises because the hydroquinone of 4 tautomerizes to naphthacenone 9 in preference to reduction of molecular oxygen.