Structural modification study of mitoxantrone (DHAQ). Chloro-substituted mono- and bis[(aminoalkyl)amino]anthraquinones

• Published in: Journal of medicinal chemistry 1987-09, Vol.30 (9), p.1682-1686
• Main Authors: Zee-Cheng, Robert, Mathew, Abraham E., Xu, Pei-Ling, Northcutt, Raymond V., Cheng, C. C.
• Format: Article
• Language: English
• Subjects: Animals; Anthraquinones - therapeutic use; Leukemia L1210 - drug therapy; Leukemia P388 - drug therapy; Melanoma - drug therapy; Mitoxantrone - therapeutic use; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00392a028

A number of chloro-substituted [(aminoalkyl)amino]anthraquinones were synthesized and evaluated for their antineoplastic and cytotoxic activity. Treatment of 5,8-dichloroquinizarin with substituted amines in pyridine resulted in the replacement of one halogen atom by the amino group to yield mainly 1-chloro-5,8-dihydroxy-4-(substituted amino)anthraquinones. On the other hand, reaction between the dichloroquinizarin and the amines in butanol gave predominantly 1,4-dichloro-5-hydroxy-8-(substituted amino)anthraquinones. Other compounds in this series were prepared by displacement of chloro, nitro, or tosyl functions of the appropriate anthraquinone derivatives with various amines by conventional methods. 1,4-Dichloro-5-hydroxy-8-[[2-[(2-hydroxyethyl)amino]ethyl]amino] anthraquinone (6b) possesses the highest inhibitory activity against P388 leukemia. Its inhibitory action against B16 melanoma and against the in vitro L1210 screen is also significant. Several other chloro- and hydroxy-substituted aminoanthraquinones (5a, 5b, and 6a) also showed noticeable activity against P388 in vivo and L1210 in vitro. Structure-activity-relationship examination indicated that the hydroxyl group may contribute to the binding of certain chloroaminoanthraquinones for their biological activity and that the [2-[(2-hydroxyethyl)amino]ethyl]amino side chain seems to be the preferred substituent over other amino side chains.