Synthesis of 7-oxo-7H-naphtho[1,2,3-de]quinoline derivatives as potential anticancer agents active on multidrug resistant cell lines.

Following our earlier finding that tetracyclic anthraquinone analogs with a fused pyridone ring exhibit cytotoxic activity toward multidrug resistant tumor cells, a series of new potential antitumor agents, 7-oxo-7H-naphtho[1,2,3-de]quinoline derivatives (3, 6-8, 10-12, 14, 15, and 18), bearing one or two basic side chains and various substituents at the pyridone ring, have been synthesized. The compounds have been obtained from 1-amino-4-chloroanthraquinone or 1-aminoanthraquinone by cyclization with diethyl malonate and the subsequent reactions of the key intermediates 2, 4, and 17. The compounds exhibited cytotoxic activity toward sensitive human leukemia cell line HL-60 and against its resistant sublines HL-60/VINC (MDR1 type) and HL-60/DX (MRP1 type).

Synthesis and biological evaluation of 2,7-Dihydro-3H-dibenzo[de,h]cinnoline-3,7-dione derivatives, a novel group of anticancer agents active on a multidrug resistant cell line.

A series of anthrapyridazone derivatives with one or two basic side chains at various positions in the tetracyclic chromophore have been synthesized. The key intermediates in the synthesis are 2,7-dihydro-3H-dibenzo[de,h]cinnoline-3,7-diones 1, 12 and 15 monosubstituted at position 2 (4d, 16a-e), or 6 (2a-f) or disubstituted at positions 2 and 6 (4a-c) or 2 and 8 (17a-e) with appropriate alkylaminoalkylamines. All analogues showed in vitro cytotoxic activity against murine leukemia (L1210) and human leukemia (K562) cell lines.

Effect of modification of 6-[(aminoalkyl)amino]-7H-benzo[e]-perimidin-7-ones on their cytotoxic activity toward sensitive and multidrug resistant tumor cell lines. Synthesis and biological evaluation.

Benzoperimidines, a novel group of antitumor anthracenedione analogues, are of interest due to their ability to overcome multidrug resistance of tumor cells (Stefańska, B., Dzieduszycka, M., Bontemps-Gracz, M.

8,11-dihydroxy-6-[(aminoalkyl)amino]-7H-benzo[e]perimidin-7-ones with activity in multidrug-resistant cell lines: synthesis and antitumor evaluation.

The synthesis of dihydroxybenzoperimidine derivatives, which are chromophore-modified dihydroxyanthracenediones with an additional pyrimidine ring incorporated into the chromophore, is reported. These derivatives are structurally related to the antitumor agent mitoxantrone. Their synthesis was carried out by the reaction of 6-amino-8,11-dihydroxy-7H-benzo[e]perimidin-7-one (5) or 6,8, 11-trihydroxy-7H-benzo[e]perimidin-7-one (10) with a number of respective (alkylamino)alkylamines.

The role of structural factors of anthraquinone compounds and their quinone-modified analogues in NADH dehydrogenase-catalysed oxygen radical formation.

Anthraquinone compounds belong to the most important class of clinical antitumour agents. However, their use is limited by their peroxidating activity, being the consequence of free radical formation initiated by three oxyreductases. This activity is considered to be the main cause of cardiotoxic effects.

6-[(aminoalkyl)amino]-substituted 7H-benzo[e]perimidin-7-ones as novel antineoplastic agents. Synthesis and biological evaluation.

A class of chromophore-modified anthracenediones with an additional pyrimidine ring incorporated into the chromophore system has been obtained in an attempt to provide compounds with diminished peroxidation activity and thus potentially lowered cardiotoxicity. Their synthesis was carried out by the reaction of 6-amino- or 6-hydroxy-7H-benzo[e]perimidin-7-one with a number of alkylamines. Potent activity was demonstrated in vitro against murine L1210 leukemia cells (equipotent with ametantrone) as well as against P388 leukemia in vivo (% T/C = 130-255).

Molecular determinants of singlet oxygen binding by anthraquinones in relation to their redox cycling activity.

A series of model anthraquinones with varying symmetry of pi-electron density distribution have been examined to verify our previous hypothesis concerning the essential role of quinone-singlet oxygen complex formation by asymmetric anthraquinones in their peroxidating properties. Comparison of the results of enzymatic studies using NADH dehydrogenase with those of cyclovoltammetric measurements fully confirmed the assumption that one-electron transfer mediation is facilitated by the preceding quinone-oxygen complex formation. To extend the scope of the molecular determinants of oxygen binding found in our previous studies, CNDO/2 and molecular electrostatic field (MEF) calculations have been performed.

Synthesis, peroxidating ability, and antineoplastic evaluation of 1-[(aminoalkyl)amino]-4-hydroxy-10-imino-9-anthracenones.

A novel group of cytotoxic anthraquinone derivatives, 1-[(aminoalkyl)amino]-4-hydroxy-10-imino-9-anthracenones, has been synthesized. It has been shown that imino analogues of the anthracenediones exhibit diminished ability to generate oxygen radicals. The cytotoxic activity of iminoanthracenones obtained was lower than that of the related quinone carbonyl analogues.

Synthesis of unsymmetrically substituted 1,4-bis[(aminoalkyl)amino]anthracene-9,10-diones as potential antileukemic agents.

The synthesis of unsymmetrically substituted 1,4-bis[(aminoalkyl)amino]anthracene-9,10-diones bearing one "mitoxantrone side arm" and another (aminoalkyl)amino moiety has been described. These unsymmetrical anthracene-9,10-diones exhibit cytotoxic activity against L1210 leukemia cells and antitumor activity against P388 leukemia in mice.

Synthesis and antineoplastic evaluation of 1,4-bis(aminoalkanamido)-9,10-anthracenediones.

The effect of the replacement of amino groups, attached to the anthraquinone ring in [(aminoalkyl)amino]-anthraquinones, by an amido function on DNA binding, cytotoxicity, and antileukemic activity has been studied. The corresponding 1,4-bis(aminoalkanamido)-9,10-anthracenediones have been synthesized and examined. It has been concluded that such modification does not exclude the DNA binding and cytotoxicity of mentioned compounds but decreases or abolishes the in vivo antileukemic activity.

Synthesis and antileukemic activity of N-enamine derivatives of daunorubicin, 5-iminodaunorubicin, and doxorubicin.

Eleven N-enamine derivatives of daunorubicin and of its 5-imino analogue as well as of doxorubicin have been synthesized and evaluated for antileukemic activity in vitro and in vivo. Comparison of biological activities of examined compounds with other enamine derivatives of daunorubicin, reported earlier by us, has indicated that the optimal activity is shown by N-(1-carboethoxypropen-1-yl-2)daunorubicin.

New N-amino acid derivatives of daunorubicin.

New N-amino acid derivatives of daunorubicin have been obtained by acylation of daunorubicin amino group with alpha, beta, and gamma amino acids and their N,N-dibenzyl derivatives. The results of the antitumor activity determination have evidenced that the change of the amino function position in the daunorubicin derivatives, in relation to that of the parent antibiotic, causes the loss of activity.