New Anthracenediones with Potential Anticancer Activity: Synthesis and Characterization of Bis‐diethylaminopropionamido Derivatives

Abstract

A number of new anthracenedione derivatives has been synthesized, which bear two charged side chains at different positions of the fused ring The synthetic route included preparation of nitro-derivatives, which were reduced to the corresponding amino-derivatives, acylated with haloacyl halides and finally transformed into the tertiary amino analogues using the appropriate secondary amine. The new anthracenediones exhibit outstanding inhibition of cell proliferation in vitro. Some of them are promising in view of an application as anticancer drugs.sprechenden Aminen reduziert, Diese wurden dann mit Chlorpropionylchlorid acyliert und endlich mit Diethylamin umgesetzt. Die neuen Derivate sind sehr aktiv in vitro und k6nnten gegen Krebs niitzlich sein.Many 9,lO-anthracenedione derivatives have been synthesized in recent years. Besides the anthracycline antiliiotics, ametantrone and mitoxantrone deserve to be mentioned for their antineoplastic activity', *I. The latter compounds bear two charged hydroxyethylaminoethyl side chains at positions 1 and 4 of the fused ring system.To investigate the effects of substitution at different positions of the aromatic planar moiety and/or the effects of the nature of the side-chain substituents, we synthesized the new bis-substituted 9,lO-anthracenediones reported in chart 1. dihydroxy-9,1O-anthracenedione, precursor of compound 2, was synthesized in our laboratory following two different routes reported in the lit.33 4! However, the yield was always unsatisfactory, as different. products are obtained, which cannot be separated easily.The synthesis of compound 3 has been performed starting from 1,8-dihydroxy-2,4-dinitro-9,lO-anthracenedione, obtained by 'nitration of 1,8-dihydroxy-9,1O-anthracenedione and subsequent reduction with Sn/SnCl, in HCl to the cor- Results and Discussion responding 2,4-diamino derivative. Finally, 4-amino-l-h~-droxy-9,lO-anthracenedione has been utilized to prepare 2,4-To obtain the final products containing diethylaminopro-diamino-l-hydroxy-9,1O-anthracenedione, precursor of compound 4 according to the following sequence: acetylation of the amino group, nitration of the anthraquinone ring, reduction of the nitro group and hydrolysis of the N-acetyl moiety.pionamidogroups at the desired positions of the anthraquinone ring, the appropriate amino anthraquinones were used. Only the precursor of compound 1, 1,4-diamino-9,10-anthracenedione, was a commercial sample.