Adriamycin analogues. Synthesis of the α and β anomers of 7-O-(3-amino-3,5-dideoxy-D-ribofuranosyl)adriamycinone and some related compounds

Abstract

2-O-Acetyl-3,5-dideoxy-3-trifluoracetamido-D-ribofuranosyl bromide, prepared by an improved 10-step synthesis from 1,2-isopropylidene-D-xylofuranose, was coupled under Koenigs–Knorr glycosidation conditions with a side-chain protected aglycone derivative of the antitumor antibiotic adriamycin. Complete removal of the blocking groups from the anomeric coupling products afforded glycoside ring-contracted analogs of adriamycin. Selective removal of blocking groups resulted in analogs of N-trifluoroacetyladriamycin-14-valerate (AD 32), an non-DNA binding analog of adriamycin with clinical activity and reduced toxicity. Anomeric assignment of coupling products was derived from nmr spectral data consistent with Karplus equation considerations. In vitro growth-inhibition and DNA binding assays were performed with a number of the target compounds. Of interest is the observation that, although binding to calf thymus DNA to a lesser extent than adriamycin, the isosteric 7-O-(3-amino-3,5-dideoxy-β-D-ribofuranosyl)adriamycinone produced a greater inhibition of growth of CCRF–CEM human-derived lymphoblastic leukemic cells in culture.