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

• Published in: Journal of medicinal chemistry Vol. 25; no. 1; pp. 18 - 24
• Main Authors: Mosher, Carol W, Wu, Helen Y, Fujiwara, Allan N, Acton, Edward M
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 01.01.1982
• Subjects: Animals; Antibiotics, Antineoplastic - chemical synthesis; Antibiotics, Antineoplastic - pharmacology; Daunorubicin - analogs & derivatives; Daunorubicin - pharmacology; DNA, Neoplasm - biosynthesis; Leukemia L1210 - metabolism; Leukemia P388 - drug therapy; Mice; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00343a004

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.