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

Abstract

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.

Aminoacyl-analogues of mitoxantrone as novel DNA-damaging cytotoxic agents

“…In fact, the importance of side-chain OH groups in improving the activity of Mx is well known, 20 the replacement with amino residues leading to less effective compounds. 25 The DNA-binding affinity for KAQs increases 6-fold when using poly(dG-dC) instead of poly(dA-dT), whereas this preference is reduced to a factor of 2-3 in the VAQ series. For Mx a preference factor of ISSN 1424-6376 Page 213 © ARKAT USA, Inc about 3 has been reported.…”

Synthesis and calculated properties of some 1,4-bis(amino)anthracene-9,10-diones

“…1,4-Bis(n-propylamino)-5,8-dichloroanthracene-9,10-dione (1e) 2,3-Dihydro-9,10-dihydroxy-5,8-dichloroanthracene-1,4-dione (1.00 g, 3.2 mmol) was added to a solution of n-propylamine (1.00 g, 17 mmol) in ethanol (25 ml) and the mixture was heated for 1 h at 50-55 • C. The solution was allowed to cool, petroleum ether 40-60 (25 ml) was added and the mixture stirred overnight. The resulting solid was filtered off and purified via column chromatography using an eluant of toluene 95% and chloroform This journal is © The Royal Society of Chemistry 2006 5% to yield the title compound (0.60 g, 48%), mp 150 2,3-Dihydro-9,10-dihydroxy-5,8-dichloroanthracene-1,4-dione (1.00 g, 3.2 mmol) was added to a solution of 20% methylamine in water (4.96 g, 32 mmol) and the mixture was heated for 1 h at 50-55 • C. The solution was allowed to cool, the resulting precipitate filtered off, washed with water (50 ml) and purified by column chromatography using an eluant of toluene 95% and chloroform 5% to yield the title compound (0.50 g, 47%), mp 145 67 2,3-Dihydro-9,10-dihydroxy-5,8-dichloroanthracene-1,4-dione (1.00 g, 3.2 mmol) was added to a solution of N,Ndimethylethylenediamine (2.8 g, 32 mmol) in ethanol (25 ml) and the mixture was heated for 2 h at 50-55 • C. The solution was allowed to cool, petroleum ether 40-60 (25 ml) was added and the mixture further cooled with ice. The resulting precipitate was filtered off, added to a solution of diethyl ether (25 ml) and methanol (25 ml) saturated with hydrogen chloride gas and stirred for 15 min.…”

Synthesis and Human Telomerase Inhibition of a Series of Regioisomeric Disubstituted Amidoanthraquinones

“…Mitoxantrone and ametantrone are antitumor 1,4-bis[(aminoalkyl)amino]anthraquinones that were discovered by molecular simplification of the anthracycline pharmacophore. [13][14][15] However, adriamycin (doxorubicin, Chart 1) has structural characteristics that limit its efficacy and safety. New anthracyclines with distinct structure, pharmacokinetics, pharmacodynamics, and toxicity profiles have been developed to overcome the limitations of doxorubicin and to further exploit the activity of anthracyclines.…”