Chromophore-Modified Antitumor Anthracenediones: Synthesis, DNA Binding, and Cytotoxic Activity of 1,4-Bis[(aminoalkyl)amino]benzo[g]phthalazine-5,10-diones

Abstract

As part of a program aimed at exploring the effect of the introduction of heteroatoms into the anthracene-9,10-dione chromophore, we have synthesized novel 1,4-bis[(aminoalkyl)amino]-benzo[g]phthalazine-5,10-diones (BPDs) 1 which are related to the antitumor agents ametantrone and mitoxantrone. Derivatives 1 were prepared by chromic acid oxidation of acylated benzo[g]phthalazines 5 followed by acid hydrolysis or by silylation-amination of 5,10-dihydroxybenzo[g]phthalazine-1,4-dione (8). The 1-[(aminoalkyl)amino]-4-amino congeners 2 were isolated in low yields as byproducts from the oxidation of 5. Against a panel of human tumor cell lines, the benzo[g]phthalazine-5,10-diones 1 and 2 exhibited cytotoxic activity comparable or even superior to that of mitoxantrone. In compounds 1, structure-activity relationships different than those operative in the carbocyclic series appeared to emerge. DNA-binding studies with the ametantrone-like compound 1c and its single-armed congener 2c indicated that the introduction of a 2,3-diaza subunit into the anthracene-9,10-dione chromophore reduces the affinity of the drug for DNA in comparison with ametantrone. On the other hand, the number of side-chain groups does not affect binding to a great extent. These findings seem to suggest mechanisms of cell death other than those induced by simple interaction of the 1,4-BPDs 1 and 2 with DNA.

Design and Synthesis of Estrarubicin: a Novel Class of Estrogen-Anthracenedione Hybrids

“…vacuo. The residue (0.036 g) was flash-chromatographed (silica gel, 80Ϫ90% chloroform in petroleum ether) to give 12 (0.010 g) and Dione 11: To a stirred solution of 9 (0.210 g, 0.345 mmol) in acetic acid (5 ml) at room temp., Pb(OAc) 4 (0.184 g, 0.414 mmol) a red solid (0.012 g, 52% yield based on recovered starting material); R f ϭ 0.65 (silica gel, 35% ethyl acetate in petroleum ether); was added. After 3 h, the mixture was partitioned between CHCl 3 and water.…”

“…plastic activity due to its DNA strand cleavage ability [3] . As a consequence, great effort has been devoted both to the synthesis of the natural products themselves and to the development of new analogs [4] . Recently, attempts have been made to increase the organ and/or tissue specificity of anticancer agents by linking them to various steroidal hormones [5] .…”

“…Reagents and conditions: (a) 1.2 equiv. of Pb(OAc) 4 , then clarified by an ROESY [19] spectrum ( Figure 1 Therefore the only difference between 7 and 8 should reside in the stereochemistry of the epoxide ring. Accordingly, the reductive deoxygenation of the oxirane group of both 7 and 8, with zinc in acetic acid, produced the same compound 9 (Scheme 1).…”

Synthesis and biological evaluation of anthra[1,9-cd]pyrazol-6(2H)-one scaffold derivatives as potential anticancer agents

“…To overcome the drawback of cardiotoxic effects, a pyrazole ring is fused to the anthraquinone moiety, giving a tetracyclic system in an attempt to reduce toxicity or modify the activity of the lead compound, and may alter the metabolism of the lead (Krapcho et al 1985;Krapcho et al 1994;Gandolfi et al 1995). Losoxantrone , is an anthrapyrazole derivative and found that sharing similar pharmacokinetics (Graham et al 1992), behaving almost similarly in the in vitro National Cancer Institute (NCI) cell screen and exhibiting the same anticancer spectrum of activity as MX with reduced cardiotoxicity (Leteurtre et al 1994).…”

Synthesis of new pyrido[4,3- g and 3,4- g]quinoline-9,10-dione and dihydrothieno[2,3- g and 3,2-g]quinoline-4,9-dione derivatives and preliminary evaluation of cytotoxic activity

“…2 In this sense, the introduction of heteroatom (N, order to increase their therapeutic index. [3][4][5] These bioisosteres retain the planarity, spatial, and electronic characteristics required for molecular recognition at the cellular level and would clearly differ from their carbocyclic counterparts in their interaction with specific targets as well as in their reduction potential.…”