New anthracenedione derivatives: Interaction with DNA and biological effects

Palumbo, Manlio; Antonello, C; Viano, I; Santiano, M; Gia, Ornella; Gastaldi, Stéphane; Magno, Sebastiano Marciani

doi:10.1016/0009-2797(83)90050-9

Cited by 11 publications

(1 citation statement)

References 19 publications

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“…In MX and active congeners, the substituents are linked to the anthraquinone structure via amino linkages. We have recently started to explore the changes in the physicochemical and biological properties of substituted anthraquinones, exhibiting an amide linkage between the planar ring system and the side-chain substituents. − Since some of the compounds retain a remarkable biological activity, this class appears to be worthy of further examination.…”

Section: Introductionmentioning

confidence: 99%

Peptidyl Anthraquinones as Potential Antineoplastic Drugs: Synthesis, DNA Binding, Redox Cycling, and Biological Activity

Gatto¹,

Zagotto²,

Sissi³

et al. 1996

J. Med. Chem.

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A series of new compounds containing a 9,10-anthracenedione moiety and one or two peptide chains at position 1 and/or 4 have been synthesized. The amino acid residues introduced are glycine (Gly), lysine (Lys), and tryptophan (Trp), the latter two in both the L- and D-configurations. The peptidyl anthraquinones maintain the ability of intercalating efficiently into DNA, even though the orientation within the base-pair pocket may change somewhat with reference to the parent drugs mitoxantrone (MX) and ametantrone (AM). The interaction constants of the mono-, di-, and triglycyl derivatives are well comparable to those found for AM but 5-10 times lower than the value reported for MX. On the other hand, the glycyl-lysyl compounds bind DNA to the same extent as (L-isomer) or even better than (D-isomer) MX. As for the parent drugs without peptidyl chains, the new compounds prefer alternating CG binding sites, although to different extents. The bis-Gly-Lys derivatives are the least sensitive to base composition, which may be due to extensive aspecific charged interactions with the polynucleotide backbone. As far as redox properties are concerned, all peptidyl anthraquinones show a reduction potential very close to that of AM and 60-80 mV less negative than that of MX; hence, they can produce free-radical-damaging species to an extent similar to the parent drugs. The biological activity has been tested in human tumor and murine leukemia cell lines. Most of the test anthraquinones exhibit cytotoxic properties close to those of AM and considerably lower than those of MX. Stimulation of topoisomerase-mediated DNA cleavage is moderately present in representatives of the glycylanthraquinone family, whereas inhibition of the background cleavage occurs when Lys is present in the peptide chain. For most of the test anthraquinones, the toxicity data are in line with the DNA affinity scale and the topoisomerase II stimulation activity. However, in the lysyl derivatives, for which lack of cytotoxicity cannot be related to poor binding to DNA, the steric and electronic properties of the side-chain substituent must impair an effective recognition of the cleavable complex.

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Section: Introductionmentioning

confidence: 99%

Peptidyl Anthraquinones as Potential Antineoplastic Drugs: Synthesis, DNA Binding, Redox Cycling, and Biological Activity

Gatto¹,

Zagotto²,

Sissi³

et al. 1996

J. Med. Chem.

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Potential Antitumor Agents, XV. Anthraquinone Derivatives

Andreani

Rambaldi

Bonazzi

et al. 1985

Archiv der Pharmazie

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

Antonello¹,

Uriarte²,

Palumbo³

1988

Archiv der Pharmazie

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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.

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New anthracenedione derivatives: Interaction with DNA and biological effects

Cited by 11 publications

References 19 publications

Peptidyl Anthraquinones as Potential Antineoplastic Drugs: Synthesis, DNA Binding, Redox Cycling, and Biological Activity

Peptidyl Anthraquinones as Potential Antineoplastic Drugs: Synthesis, DNA Binding, Redox Cycling, and Biological Activity

Potential Antitumor Agents, XV. Anthraquinone Derivatives

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

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