Enhanced antitumor properties of 3'-(4-morpholinyl) and 3'-(4-methoxy-1-piperidinyl) derivatives of 3'-deaminodaunorubicin

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Abstract
Reductive N,N-dialkylation of daunorubicin with 2,2''-oxydiacetaldehyde and NaBH3CN occurred in 2 steps without interruption and with cyclization to form 3''-(4-morpholinyl)-3''-deaminodaunorubicin. This derivative retained the antitumor efficacy of doxorubicin against mouse leukemia P388 but at 1/40 the dose; hence, it is the most potent anthracycline analog synthesized so far. The 4-methoxy-1-piperidinyl derivative, similarly prepared with 3-methoxyglutaraldehyde, showed improved efficacy against P388, though at normal doses. Results with a series of analogues indicate that incorporation of the N in the new ring and the presence of an ether O at the 4-position are critical for enhanced activity.