28008-51-7Relevant articles and documents
Reductive transformations of 10-deoxydaunomycinone
Brand,Fisher
, p. 2518 - 2530 (2007/10/02)
An enzyme system consisting of spinach ferredoxin-NADP+ reductase (ferredoxin reductase; EC 1.18.1.2) and pig heart isocitric dehydrogenase(NADP+) (isocitric dehydrogenase; EC 1.1.1.42), along with spinach ferredoxin and either of the coenzymes NAD(P)H, was utilized in the reduction of aqueous anaerobic solutions of daunomycin and related aglycons. Typically, reductive transformations of daunomycin yielded three major and several minor aglycon products, as detected by reverse-phase liquid chromatography analysis. The ferredoxin reductase component of the enzymatic system elicited the reductive deglycosylation of the daunomycin. Subsequent to the loss of the daunosamine sugar were several keto-enol tautomeric equilibria of the hydroquinone intermediates that result in the transformation of the anthracycline ring system in a fashion identical with that observed during the sodium dithionite reduction of daunomycin (Brand, D.J.; Fisher, J.J. Am. Chem Soc. 1986, 108, 3088-3096). Additionally, an aldo-keto reductase contaminant in the isocitric dehydrogenase enzyme preparation caused the stereoselective reduction of the acetyl side chain found in daunomycin and related aglycons, resulting in all the product aglycons having a 1-hydroxyethyl side chain bearing an S configuration at the C-1' stereogenic center. The three major products of the ferredoxin reductase and isocitric dehydrogenase enzyme-catalyzed reduction of daunomycin have been characterized. Two of the major products of the reaction, [S-(R*,S*)]-1,2,3,4-tetrahydro-2,11-dihydroxy-2-(1-hydroxyethyl)-7 -methoxy-5,12-naphthacenedione (16; 50-55% of the product) and [S-(R*,S*)]-1,2,3,4-tetrahydro-2,6-dihydroxy-2-(1-hydroxyethyl)-7 -methoxy-5,12-naphthacenedione (17; 15-20% of the product), involve both the loss of an oxygen from the anthracycline's C ring and the reduction of the side-chain acetyl group. The third major product and two of the minor products were a diastereomeric set of ''leuco'' tautomers of the hydroquinone produced upon reduction of the anthracycline ring system; reduction of the acetyl side chain also occurred. These three diastereomers of [2R-[2α,2(S*)]]-1,2,3,4,4a,12a-hexahydro-2,6,11-trihydroxy-2-(1- hydroxyethyl)-7-methoxy-5,12-naphthacenedione differ in the stereochemistry at the C-4a, C-12a ring juncture. The major diastereomer (19; 20-25% of the product) has a trans ring juncture, while the two minor diastereomers (20 and 21; 0-3% and 5-8% of the product) have a cis ring juncture. Virtually identical results were observed when either daunomycinone or (1'S)-1'-dihydrodaunomycinone (11), instead of daunomycin, were used as a substrate for the enzyme system. However, a chromatographically different set of products, epimeric to those formed when (1'S)-1'-dihydrodaunomycinone was the substrate, were produced when (1'R)-1'-dihydrodaunomycinone (12) was used. All of these products had the R configuration at the C-1' stereogenic center. This series of results may prove of value in the synthetic preparation of 1'-anthracyclinols and in the study of the possible role of 1'-anthracyclinol aglycons and glycosides in the expression of the anthracycline's dose-limiting cardiotoxicity.
