Synthesis and antitumor activity of 4'-O-methyldaunorubicin, 4'-O-methyladriamycin, and their 4'-epi analogs

Journal of Medicinal Chemistry
1979.0

Abstract

The synthesis of analogues of daunorubicin (1) and doxorubicin (2) in which the amino sugar moiety is functionally and/or configurationally modified is of interest in relation to structure-activity relationships, which, in turn, may lead to new and improved drugs. In our continuing concern with new anthracyclines, we now report the synthesis and preliminary biological data of 4'-O-methyldaunorubicin (3), 4'-O-methyladriamycin (4), 4'-epi-4'-O-methyldaunorubicin (5), and 4'-epi-4'-O-methyladriamycin (6). The new glycosides 3 and 4 have the natural amino sugar, daunosamine (3-amino-2,3,6-trideoxy-L-lyxo-hexose), replaced by the corresponding 4-O-methyl analogue which was prepared from methyl N-(trifluoroacetyl)-α-L-daunosaminide (7). Compounds 5 and 6 are new anthracycline glycosides containing actinosamine (3-amino-2,3,6-trideoxy-4-O-methyl-L-arabino-hexose), an amino sugar constituent of the antibiotic actinoidin. Comparison of biological activity of the new analogues with the parent antibiotics on P-388 or L-1210 leukemias in mice is reported in Tables I and II. The new compounds 3–6 retain the antitumor activity of the parent drugs, compound 4 appearing of particular interest because of the high efficacy shown.

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