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J Med Chem. 1986 Jul;29(7):1215-21.

7-Deoxydaunomycinone quinone methide reactivity with thiol nucleophiles.

Abstract

Under anaerobic conditions and with NADPH as a reducing agent, daunomycin is reduced in the presence of spinach ferredoxin: NADP+ oxidoreductase as the enzyme catalyst to its hydroquinone, from which intramolecular elimination of the C-7 glycoside proceeds to provide a quinone methide intermediate. This quinone methide is capable of bimolecular reaction with the thiolate nucleophiles N-acetyl-L-cysteine, N-(tert-butoxycarbonyl)-L-cysteine, and 1-thio-beta-D-glucose, providing a pair of C-7 diastereomers, when the reaction is carried out under the autocatalytic conditions offered by substoichiometric quantities of NADPH. With 0.4 equiv of NADPH, optimal yields of the adducts are obtained of approximately 65%. In each case, the 7S adduct is the major product, with the observed stereoselectivities (7S to 7R) ranging from 2.6 to 1 for N-acetyl-L-cysteine to 4 to 1 for both the N-(tert-butoxycarbonyl)-L-cysteine and 1-thio-beta-D-glucose as nucleophiles. By standard blocking and deblocking procedures, the complete set of complementary functionalized (7S)- and (7R)-N-acetyl and O-methyl 7-L-cysteinyl-7-deoxydaunomycinones is prepared. All efforts to extend this quinone methide trapping reaction to additional nucleophiles (such as I- or N3-), including the use of Fe(III) chelation, are unsuccessful. The Fe(III) chelate of daunomycin is however reduced by ferredoxin reductase and NADPH to the Fe(III) chelate of 7-deoxydaunomycinone, suggesting that quinone reduction of the chelate to the quinone methide has occurred. Of the new compounds prepared, only (7R)-7-S-(beta-D-glucopyranosyl)-7-thio-7-deoxydaunomycinone has biological activity. As an in vitro inhibitor of P388 cell growth, it has a 50% inhibitory concentration 25 times greater than that of daunomycin.

PMID:
3806571
DOI:
10.1021/jm00157a017
[Indexed for MEDLINE]

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