Intensely potent morpholinyl anthracyclines

Abstract

3''-Deamino-3''-(3-cyano-4-morpholinyl)doxorubicin is a new analog that is 100-1000 times more potent than doxorubicin against tumors in cell culture or in mice, that is active by i.p., i.v., or oral dosing, and that does not produce chronic myocardial lesions in mice. This analog was encountered in studies on the reductive alkylation of doxorubicin and daunorubicin with 2,2''-oxybis[actaldehyde], which constructs a morpholino ring incorporating the amino N. The morpholinyl nitrile byproducts are separated by virtue of their nonbasicity from the expected morpholino derivatives. The 13-dihydro and 5-imino derivatives are also described in this important new class of anthracyclines.