Enhanced antitumor properties of 3'-(4-morpholinyl) and 3'-(4-methoxy-1-piperidinyl) derivatives of 3'-deaminodaunorubicin.
Reductive N,N-dialkylation of daunorubicin with 2,2'-oxydiacetaldehyde and NaBH3CN occurred in two 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 one-fortieth the dose; hence, it is the most potent anthracycline analogue 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.
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis / Q000494:pharmacology*; D004273:DNA, Neoplasm / Q000096:biosynthesis; D003630:Daunorubicin / Q000031:analogs & derivatives* / Q000494:pharmacology; D007939:Leukemia L1210 / Q000378:metabolism; D007941:Leukemia P388 / Q000188:drug therapy; D051379:Mice; D013329:Structure-Activity Relationship
D000903:Antibiotics, Antineoplastic; D004273:DNA, Neoplasm; C034843:3'-(4-methoxy-1-piperidinyl)-3'-deaminodaunorubicin; C034844:3'-(4-morpholinyl)-3'-deaminodaunorubicin; D003630:Daunorubicin